CN106177958A - Comprise DPP 4 inhibitor (BI 1356) and optionally combine the antidiabetic medicine of other antidiabetic drug - Google Patents

Comprise DPP 4 inhibitor (BI 1356) and optionally combine the antidiabetic medicine of other antidiabetic drug Download PDF

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Publication number
CN106177958A
CN106177958A CN201610580276.0A CN201610580276A CN106177958A CN 106177958 A CN106177958 A CN 106177958A CN 201610580276 A CN201610580276 A CN 201610580276A CN 106177958 A CN106177958 A CN 106177958A
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China
Prior art keywords
inhibitor
dpp
antidiabetic drug
pharmaceutical composition
optionally
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CN201610580276.0A
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E.U.格雷弗-莫迪
H-J.沃伊尔勒
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Boehringer Ingelheim International GmbH
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Boehringer Ingelheim International GmbH
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    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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Abstract

The present invention relates to antidiabetic medicine, it is particularly suited for one or more diseases in treatment or prevention type i diabetes, type ii diabetes, glucose tolerance reduction and hyperglycemia.Moreover, it relates to prevent or treat dysbolismus and the method for associated conditions.Described medicine is to use the single therapy of DPP 4 inhibitor (preferably BI 1356) or use DPP 4 inhibitor and the second and/or the combined therapy of the third antidiabetic drug.

Description

Comprise DPP-4 inhibitor (BI 1356) and optionally combine other antidiabetic drug Antidiabetic medicine
The application is Chinese Patent Application No. 201080016144.6 (denomination of invention: comprise DPP-4 inhibitor (Li Lalie Spit of fland) optionally combine the antidiabetic medicine of other antidiabetic drug, the applying date: on February 12nd, 2010) divisional application.
Technical field
The present invention relates to DPP-4 inhibitor, it is suitable to treatment or prevents one or more to be especially selected from type i diabetes, II Patients with type Ⅰ DM, glucose tolerance reduction, impaired fasting glucose and the disease of hyperglycemia, and relate to comprising defined herein The pharmaceutical composition of DPP-4 inhibitor and optionally one or more other active substance materials or combination, relate to it Purposes in treatment dysbolismus, especially as antidiabetic medicine.
Additionally, the method that the present invention relates to realize following purpose in the patient needed:
-prevention dysbolismus, slow down the progress of this dysbolismus, postpone or treat this dysbolismus；
-improve glycemic control and/or reduce fasting plasma glucose, Post-prandial plasma glucose and/or the blood red egg of glycosylation White HbA1c；
-prevent, slow down, postpone or the reduction of reverses glucose tolerance, impaired fasting glucose, insulin resistant and/or metabolism Septic syndrome becomes type ii diabetes；
-prevention selected from diabetic complication disease or obstacle, slow down this disease or obstacle progress, postpone or treat this disease Disease or obstacle；
-reduce body weight and/or body fat or prevention body weight and/or body fat increase or promote to reduce body weight and/ Or body fat；
-prevent or treat pancreatic beta cell degenerate and/or improve and/or recover or protection pancreatic beta cell function and/ Or recover pancreatic insulin secretory function；
-prevent, slow down, postpone or treat and extremely accumulated the disease caused or disease by liver or ectopic fat；
-be used for keeping and/or improve insulin sensitivity and/or treatment or prevention hyperinsulinemia and/or insulin Opposing；
The diabetes (NODAT) of-prevention new outbreak after transplanting and/or the metabolism syndrome (PTMS) after transplanting, slow down this A little disease progression, postpone or treat these diseases；
-prevent, postpone or reduce NODAT and/or PTMS related complication, including blood capillary and macrovascular diseases and thing Part, transplant rejection, infection and death；
-treatment hyperuricemia and hyperuricemia associated conditions；
It is characterized in that DPP-4 inhibitor defined below optionally with one or more other active substance combination to Medicine.
Additionally, the present invention relates to DPP-4 inhibitor purposes in the medicine prepared in method described in context.
The medicine for the method described in context is being prepared in the pharmaceutical composition or the combination that the invention still further relates to the present invention In purposes.
The invention still further relates to DPP-4 inhibitor defined herein, it is for the method described in context, and described method includes Give described DPP-4 inhibitor, optionally with one or more other active substances (such as its be selected from described herein those) Combination gives patient.
Background of invention
Type ii diabetes is the disease of increased popularity, and it causes life expectancy significantly to shorten because of high-frequency complication. Because the microvascular complication that diabetes are relevant, type ii diabetes is the blindness of adult onset, renal failure in industrial world at present And the most common cause of amputation.Additionally, the existence of type ii diabetes and the risk of cardiovascular disease increase by 2 to 5 times are relevant.
After disease continues for a long time, the oral therapies ultimate failure of most of type ii diabetes patients, and become islets of langerhans Element dependency, it is necessary to every day insulin injection and carry out repeatedly glucose measurement every day.
The perspective diabetes study of Britain (United Kingdom Prospective Diabetes Study, UKPDS) Prove with metformin, sulfonylureas or insulin intensive treatment only produce limited glycemic control improve (HbA1c difference be about 0.9%).Even if additionally, in the patient of intensive treatment group, glycemic control significantly deteriorates, this is owing to β cell merit Can degenerate caused.Importantly, intensive treatment is not relevant to substantially reducing of macrovascular complications (i.e. cardiovascular event).Therefore, Many type ii diabetes patients still can not fully treat, in part because the long-term efficacy of existing hyperglycemia therapy, toleration And it is administered the restriction of convenience.
In therapy (such as one line or two gamma therapies and/or monotherapy or (initial or additional (add-on)) combination treatment) Conventional oral antidiabetic thing includes, but is not limited to metformin, sulfonylureas, thiazolidinedione, row how (glinides) And alpha-glucosidase inhibitor.
It is conventionally used for parenteral antidiabetic medicine (such as one line or the two wires, and/or single or (initial or chase after for the treatment of Add) combination treatment) include but not limited to GLP-1 or GLP-1 analog, and insulin or insulin analog.
The high rate of Endodontic failure is the relevant to prolonged hyperglycemia concurrent of height ratio in type ii diabetes patient Disease or chronic injury (include blood capillary and macrovascular complications, such as diabetic nephropathy, retinopathy or neuropathy, Or cardiovascular complication) main cause.
Accordingly, there exist to have and amelioration of disease characteristic relevant to glycemic control relevant and with reduce cardiovascular morbidity And the relevant good effects of mortality rate shows the method for security situation, medicine and the pharmaceutical composition of improvement or combination simultaneously Unsatisfied needs.
DPP-4 inhibitor represent another kind of for treat or improve that the glycemic control of type ii diabetes patient researched and developed new Medicine.
Such as, DPP-4 inhibitor and application thereof is disclosed in WO 2002/068420, WO 2004/018467, WO 2004/ 018468、WO 2004/018469、WO 2004/041820、WO 2004/046148、WO 2005/051950、WO 2005/ 082906、WO 2005/063750、WO 2005/085246、WO 2006/027204、WO 2006/029769、WO2007/ 014886、WO 2004/050658、WO 2004/111051、WO 2005/058901、WO 2005/097798、WO 2006/ 068163、WO 2007/071738、WO 2008/017670、WO 2007/128724、WO 2007/128721、WO 2007/ In 128761 or WO 2009/121945.
Goal of the invention
It is an object of the invention to provide prevention dysbolismus (especially type ii diabetes), slow down entering of this dysbolismus Open up, postpone or treat medicine and/or the method for this dysbolismus.
Another object of the present invention is to provide the blood glucose control of improvement, especially type ii diabetes patient in the patient needed The medicine of system and/or method.
Although it is single to another object of the present invention is to provide improvement to carry out antidiabetic medicine (such as metformin) Although therapy or carry out the combination treatment of two or three antidiabetic drug but the blood glucose of the most insufficient patient of glycemic control The medicine controlled and/or method.
Another object of the present invention is to provide prevention, slow down or postpone glucose tolerance reduction (IGT), fasting glucose different Often (IFG), insulin resistant and/or metabolism syndrome are in progress into medicine and/or the method for type ii diabetes.
Another object of the present invention is to provide prevention selected from diabetic complication disease or obstacle, slow down this disease or Obstacle is in progress, postpones or treat this disease or the medicine of obstacle and/or method.
Another object of the present invention is to provide need patient in reduce body weight or prevention body weight increase medicine and/ Or method.
Another object of the present invention is to provide and there are the efficient new medicine treating dysbolismus, these dysbolismus It is especially diabetes, glucose tolerance reduction (IGT), impaired fasting glucose (IFG) and/or hyperglycemia, this pharmaceutical composition There is the most splendid good pharmacology and/or pharmacokinetics and/or physicochemical characteristics.
By description and the embodiment of context, those skilled in the art will become apparent from other purpose of the present invention.
Summary of the invention
Within the scope of the present invention, have discovered unexpectedly that DPP-4 inhibitor defined herein and comprise herein calmly Pharmaceutical composition or the combination of adopted DPP-4 inhibitor and optionally one or more other active substances are advantageously used for Prevent dysbolismus, slow down its progress, delay (such as postponing its outbreak) or treat this dysbolismus, be particularly useful for improving patient Glycemic control.This opens treatment and prevention type ii diabetes, overweight, obesity, diabetic syndrome and has related disorders The new treatment of state may.
Therefore the first aspect of the invention provides and comprises following pharmaceutical composition or combination:
(a) DPP-4 inhibitor, and, optionally,
(b) selected from group G3 the second antidiabetic drug, it include biguanide (especially metformin), thiazolidinedione, Sulfonylureas, row how, alpha-glucosidase inhibitor and GLP-1 analog, and, optionally,
(c) selected from group G3 the third antidiabetic drug being different from (b), it include biguanide (especially metformin), Thiazolidinedione, sulfonylureas, row how, alpha-glucosidase inhibitor and GLP-1 analog,
Or its pharmaceutically acceptable salt.
One little aspect of the present invention provides and comprises following pharmaceutical composition or combination:
(a) DPP-4 inhibitor, and, optionally,
(b) selected from group G3 the second antidiabetic drug, it include biguanide (especially metformin), thiazolidinedione, Sulfonylureas, row how, alpha-glucosidase inhibitor and GLP-1 analog, and, optionally,
C () is different from the third antidiabetic drug of (b), it is selected from metformin, sulfonylureas, pioglitazone, Luo Gelie Ketone, repaglinide, Nateglinide, acarbose, voglibose, miglitol and GLP-1 analog,
Or its pharmaceutically acceptable salt.
Another little aspect of the present invention provides and comprises following pharmaceutical composition or combination:
(a) DPP-4 inhibitor, and, optionally,
(b) the second antidiabetic drug, its selected from metformin, sulfonylureas, pioglitazone, rosiglitazone, repaglinide, Nateglinide, acarbose, voglibose, miglitol and GLP-1 analog, and, optionally,
(c) selected from group G3 the third antidiabetic drug being different from (b), it include biguanide (especially metformin), Thiazolidinedione, sulfonylureas, row how, alpha-glucosidase inhibitor and GLP-1 analog,
Or its pharmaceutically acceptable salt.
Another little aspect of the present invention provides and comprises following pharmaceutical composition or combination:
(a) DPP-4 inhibitor, and, optionally,
(b) the second antidiabetic drug, it is selected from metformin, sulfonylureas and pioglitazone, and, optionally,
C () is different from the third antidiabetic drug of (b), it is selected from metformin, sulfonylureas, pioglitazone, Luo Gelie Ketone, repaglinide, Nateglinide, acarbose, voglibose, miglitol and GLP-1 analog,
Or its pharmaceutically acceptable salt.
Another little aspect of the present invention provides and comprises following pharmaceutical composition or combination:
(a) DPP-4 inhibitor, and, optionally,
(b) the second antidiabetic drug, its selected from metformin, sulfonylureas, pioglitazone, rosiglitazone, repaglinide, Nateglinide, acarbose, voglibose, miglitol and GLP-1 analog, and, optionally,
C () is different from the third antidiabetic drug of (b), it is selected from metformin, sulfonylureas and pioglitazone,
Or its pharmaceutically acceptable salt.
Another little aspect of the present invention provides and comprises following pharmaceutical composition or combination:
(a) DPP-4 inhibitor, and, optionally,
(b) the second antidiabetic drug, it is selected from metformin and pioglitazone, and, optionally,
C () is different from the third antidiabetic drug of (b), it is selected from metformin, sulfonylureas and pioglitazone,
Or its pharmaceutically acceptable salt.
Another little aspect of the present invention provides and comprises following pharmaceutical composition or combination:
(a) DPP-4 inhibitor, and, optionally,
(b) the second antidiabetic drug, it is selected from metformin, sulfonylureas and pioglitazone, and, optionally,
C () is different from the third antidiabetic drug of (b), it is selected from metformin and pioglitazone,
Or its pharmaceutically acceptable salt.
When selecting the third antidiabetic drug (in addition to the second antidiabetic drug), the third antidiabetic drug described It is preferably selected from being different from other type of the second antidiabetic drug.It is therefore understood that the second and the third anti-diabetic Medicine is different, and preferably, they are selected from dissimilar (such as when the second antidiabetic drug is selected from biguanides, then the third resists Rezulin is preferably selected from other class).The type of antidiabetic drug is as it has been described above, such as biguanides, thiazolidinediones, sulphonyl Ureas, arrange how class, alpha-glucosidase inhibitor, GLP-1 and be similar to species etc..
An embodiment of the invention is directed to use with the monotherapy of DPP-4 inhibitor defined herein and/or relates to Comprise the DPP-4 inhibitor pharmaceutical composition as independent active component.
In the range of the combination and/or combination treatment of the present invention, detailed description of the invention relates to double combinations and/or double Weight therapy；Another embodiment relates to three recombinations and/or triple therapy.
According to a further aspect in the invention, it is provided that need patient in prevent dysbolismus, slow down its progress, postpone or The method treating this dysbolismus, described dysbolismus is selected from: type i diabetes, type ii diabetes, glucose tolerance reduce (IGT), impaired fasting glucose (IFG), hyperglycemia, post prandial hyperglycemia, overweight, obesity and metabolism syndrome, its feature Be contextual definition DPP-4 inhibitor and optionally the second and optionally the third antidiabetic drug such as with group Conjunction gives patient.
According to a further aspect in the invention, it is provided that in the patient needed, improve glycemic control and/or reduce fasting plasma The method of glucose, Post-prandial plasma glucose and/or glycosylated hemoglobin HbA1c, it is characterised in that contextual definition DPP-4 inhibitor and optionally the second and optionally the third antidiabetic drug such as give patient with combination.
The pharmaceutical composition of the present invention is for reducing (IGT), impaired fasting glucose (IFG), insulin with glucose tolerance Disease or disease that opposing and/or metabolism syndrome are correlated with also can have valuable amelioration of disease characteristic.
According to a further aspect in the invention, it is provided that prevent in the patient needed, slow down, postpone or reverses glucose tolerance Reduce the method that (IGT), impaired fasting glucose (IFG), insulin resistant and/or metabolism syndrome are in progress into type ii diabetes, It is characterized in that DPP-4 inhibitor and optionally the second and optionally the third antidiabetic drug example of contextual definition As given patient with combination.
The pharmaceutical composition of the application of the invention or combination, can improve glycemic control in the patient needed, also can control Treat those diseases that are relevant with blood sugar content increase or that caused and/or disease by this increase.
According to a further aspect in the invention, it is provided that in the patient needed, prevent following disease or obstacle, slow down this disease Disease or obstacle progress, the method that postpones or treat this disease or obstacle: diabetic complication, such as cataract and blood capillary and big Angiopathy, such as nephropathy, retinopathy, neuropathy, learning and memory are impaired, neural degeneration or cognitive disorder, painstaking effort Pipe or cerebrovascular disease, tissue ischemia, diabetic foot or ulcer, arteriosclerosis, hypertension, endothelial function disturbance, myocardial infarction, Acute coronary syndrome, unstable angina pectoris, stable angina pectoris, apoplexy, peripheral occlusive arterial disease, cardiac muscle Disease, heart failure, arrhythmia and vascular restenosis, it is characterised in that the DPP-4 inhibitor of contextual definition and optionally The second and optionally the third antidiabetic drug such as give patient with combination.Especially can treatment of diabetic nephropathy one Individual or many aspects (such as hyperperfusion, albuminuria and albuminuria (such as Microalbuminuria or High-grade Proteinuria)), slow down It is in progress or postpones or prevent it to show effect.It is micro-that term " tissue ischemia " especially comprises diabetic macroangiopathy, diabetic Vascular lesion, wound healing exception and diabetic ulcer.Term " blood capillary and macrovascular diseases " and " blood capillary and big blood vessel Complication " it is used interchangeably in this application.
In an embodiment of the invention, by give the present invention pharmaceutical composition or combination do not put on weight or Even reduce body weight.
According to a further aspect in the invention, it is provided that in the patient needed, reduce body weight and/or body fat or prevention body Weight and/or body fat increase or promote to reduce body weight and/or the method for body fat, it is characterised in that contextual definition DPP-4 inhibitor and optionally the second and optionally the third antidiabetic drug such as give patient with combination.
In an embodiment of the invention, by being administered the pharmaceutical composition of the present invention or combination, can postpone or in advance Anti-β cell degradation and β cell function reduce, the apoptosis of such as pancreatic beta cell or necrosis.Additionally, can improve or recover pancreas The function of glandular cell, and increase quantity and the size of pancreatic beta cell.Its display can be by the pharmaceutical composition of the present invention Reason, makes differentiation state and the hypertrophy normalization of the pancreatic beta cell that hyperglycemia upsets.
According to a further aspect in the invention, it is provided that prevent in the patient needed, slow down, postpone or treat pancreatic beta cell Degenerate and/or Pancreatic beta cells function reduces and/or improves and/or recover Pancreatic beta cells function and/or recovers pancreatic islet The method of element secretory function, it is characterised in that the DPP-4 inhibitor of contextual definition and optionally the second and optionally The third antidiabetic drug such as gives patient with combination.
In an embodiment of the invention, by being administered pharmaceutical composition or the combination of the present invention, it is possible to decrease or press down The exception accumulation of ectopic fat processed (ectopic fat) (the especially ectopic fat in liver).
According to a further aspect in the invention, it is provided that prevent, slow down, postpone or treat by liver or different in the patient needed The exception disease that causes of accumulation of position fat or the method for disease, it is characterised in that the DPP-4 inhibitor of contextual definition and Optionally the second and optionally the third antidiabetic drug such as with combination give patient.Different by liver or ectopic fat Often accumulate the disease caused or disease is especially selected from: common fats liver (general fatty liver), non-alcoholic fatty liver disease (NAFL), nonalcoholic steatohepatitis (non-alcoholic steatohepatitis, NASH), supernutrition induction Fatty liver, diabetic fatty liver, ethanol induction fatty liver or toxic fatty liver, especially non-alcoholic fatty liver disease (NAFL), it includes hepatic steatosis, nonalcoholic steatohepatitis (NASH) and/or hepatic fibrosis.
According to a further aspect in the invention, it is provided that need patient in prevent following disease, slow down its progress, postpone, The method weakening, treat or reversing this disease, described disease is hepatic steatosis, (liver) inflammation and/or liver fat Abnormal accumulation, it is characterised in that the DPP-4 inhibitor of contextual definition and optionally the second and optionally the third resists Rezulin such as gives patient with combination.
Another aspect of the present invention provides and keeps and/or improve insulin sensitivity and/or treatment in the patient needed Or prevention hyperinsulinemia and/or the method for insulin resistant, it is characterised in that the DPP-4 inhibitor of contextual definition and Optionally the second and optionally the third antidiabetic drug such as with combination give patient.
According to a further aspect in the invention, it is provided that the diabetes of new outbreak after prevention is transplanted in the patient needed (NODAT) metabolism syndrome (PTMS) and/or after transplanting, slow down these disease progression, postpone or treat the side of these diseases Method, it is characterised in that the DPP-4 inhibitor of contextual definition and optionally the second and optionally the third anti-diabetic Medicine such as gives patient with combination.
According to a further aspect in the invention, it is provided that prevent in the patient needed, postpone or reduce NODAT and/or PTMS The method of related complication (including blood capillary and macrovascular diseases and event, transplant rejection, infection and death), it is characterised in that The DPP-4 inhibitor of contextual definition and optionally the second and optionally the third antidiabetic drug are such as given with combination Give patient.
According to a further aspect in the invention, it is provided that in the patient needed, treat hyperuricemia and hyperuricemia is correlated with The method of disease (such as gout, hypertension and renal failure), it is characterised in that the DPP-4 inhibitor of contextual definition and optionally Ground the second and optionally the third antidiabetic drug such as give patient with combination.
According to a further aspect in the invention, it is provided that the purposes of DPP-4 inhibitor, it is real for preparing in the patient needed The medicine of following purpose:
-prevention selected from following dysbolismus, slow down the progress of this dysbolismus, postpone or treat this dysbolismus: I type Diabetes, type ii diabetes, glucose tolerance reduce (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia Disease, overweight, obesity and metabolism syndrome；Or
-improve glycemic control and/or reduce fasting plasma glucose, Post-prandial plasma glucose and/or the blood red egg of glycosylation White HbA1c；Or
-prevent, slow down, postpone or reverses glucose tolerance reduce (IGT), impaired fasting glucose (IFG), insulin resistant And/or metabolism syndrome is in progress into type ii diabetes；Or
-prevention selected from following disease or obstacle, slow down this disease or obstacle progress, postpone or treat this disease or barrier Hinder: diabetic complication, such as cataract and blood capillary and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, Tissue ischemia, arteriosclerosis, myocardial infarction, apoplexy and peripheral occlusive arterial disease；Or
-reduce body weight and/or body fat or prevention body weight and/or body fat increase or promote to reduce body weight and/ Or body fat；Or
-prevent, slow down, postpone or treat pancreatic beta cell degenerate and/or Pancreatic beta cells function reduce, and/or improve and/ Or recover Pancreatic beta cells function and/or recover pancreatic insulin secretory function；Or
-prevent, slow down, postpone or treat and extremely accumulated the disease caused or disease by liver or ectopic fat；Or
-keep and/or improve insulin sensitivity and/or treatment or prevention hyperinsulinemia and/or insulin resistant； Or
The diabetes (NODAT) of-prevention new outbreak after transplanting and/or the metabolism syndrome (PTMS) after transplanting, slow down it It is in progress, postpones or treat these diseases；Or
-prevent, postpone or reduce NODAT and/or PTMS related complication, including blood capillary and macrovascular diseases and thing Part, transplant rejection, infection and death；Or
-treatment hyperuricemia and hyperuricemia associated conditions；
This purposes is characterised by this DPP-4 inhibitor, the most individually or with the second of contextual definition with And optionally the third antidiabetic drug gives with combination.
According to a further aspect in the invention, it is provided that the purposes of the second antidiabetic drug of contextual definition, it is used for making The standby medicine realizing following purpose in the patient needed:
-prevention selected from following dysbolismus, slow down the progress of this dysbolismus, postpone or treat this dysbolismus: I type Diabetes, type ii diabetes, glucose tolerance reduce (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia Disease, overweight, obesity and metabolism syndrome；Or
-improve glycemic control and/or reduce fasting plasma glucose, Post-prandial plasma glucose and/or the blood red egg of glycosylation White HbA1c；Or
-prevent, slow down, postpone or reverses glucose tolerance reduce (IGT), impaired fasting glucose (IFG), insulin resistant And/or metabolism syndrome is in progress into type ii diabetes；Or
-prevention selected from following disease or obstacle, slow down this disease or obstacle progress, postpone or treat this disease or barrier Hinder: diabetic complication, such as cataract and blood capillary and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, Tissue ischemia, arteriosclerosis, myocardial infarction, apoplexy and peripheral occlusive arterial disease；Or
-reduce body weight and/or body fat or prevention body weight and/or body fat increase or promote to reduce body weight and/ Or body fat；Or
-prevent, slow down, postpone or treat pancreatic beta cell degenerate and/or Pancreatic beta cells function reduce, and/or improve and/ Or recover Pancreatic beta cells function and/or recover pancreatic insulin secretory function；Or
-prevent, slow down, postpone or treat and accumulated the disease or disease caused by the exception of liver or ectopic fat；Or
-keep and/or improve insulin sensitivity and/or treatment or prevention hyperinsulinemia and/or insulin resistant；
This purposes is characterised by the DPP-4 inhibitor and optionally of this second antidiabetic drug and contextual definition The third antidiabetic drug such as gives with combination.
According to a further aspect in the invention, it is provided that the purposes of the pharmaceutical composition of the present invention, it is used for up and down for preparation Therapeutic described in literary composition and the medicine of prophylactic methods.
Definition
" active component " in the pharmaceutical composition of the term present invention refers to the DPP-4 inhibitor and/or second of the present invention Plant antidiabetic drug and/or the third antidiabetic drug.
The term " Body Mass Index " of human patients or " BMI " be defined as by kilogram in terms of body weight divided by height in meters Square, the unit of such BMI is kg/m2。
Term " overweight " is defined as the BMI of individuality more than 25kg/m2And less than 30kg/m2Disease.Term " overweight " and " fat early stage " is used interchangeably.
Term " obesity " is defined as the BMI of individuality equal to or more than 30kg/m2Disease.Defining according to WHO, term is fertile Fat disease can be classified as follows: term " I level obesity " is that BMI equals to or more than 30kg/m2But less than 35kg/m2Disease；Term " II level obesity " is that BMI equals to or more than 35kg/m2But less than 40kg/m2Disease；Term " III level obesity " is BMI etc. In or more than 40kg/m2Disease.
Term " visceral obesity " be defined as measure to male's waist-to-hipratio more than or equal to 1.0 and women waist-to-hipratio more than or Disease equal to 0.8.Its definition insulin resistant and the risk of pre-diabetes development.
Term " abdominal fatness " is commonly defined as male's waistline > 40 inches or 102cm and women waistline > 35 inches or The disease of 94cm.For Japan race (Japanese ethnicity) or Japanese patients, abdominal fatness may be defined as man Property waistline >=85cm and women waistline >=90cm (for example, see Japan metabolism syndrome diagnosis enquiry committee (investig a ting committee for the diagnosis of metabolic syndrome in Japan))。
Term " blood glucose is normal " is defined as individual fasting plasma glucose concentration in normal range, i.e. more than 70mg/dL (3.89mmol/L) and less than 110mg/dL (6.11mmol/L) or the situation of 100mg/dL (5.6mmol/L)." on an empty stomach " word There is the general sense of medical terminology.
Term " hyperglycemia " is defined as individual fasting plasma glucose concentration and is higher than normal range, i.e. more than 110mg/dL (6.11mmol/L) or the disease of 100mg/dL (5.6mmol/L)." on an empty stomach " word has the general sense of medical terminology.
Term " hypoglycemia " less than 60 to 115mg/dL (3.3 to 6.3mmol/L) is just being defined as individual blood sugar concentration Often scope, the disease of especially less than 70mg/dL (3.89mmol/L).
Term " post prandial hyperglycemia " is defined as individuality 2 hours blood glucoses after the meal or serum glucose concentration more than 200mg/dL (11.11mmol/L) disease.
Term " impaired fasting glucose " or " IFG " are defined as individual fasting plasma glucose concentration or Diagnostic Value of Fasting Serum concentration of glucose exists In the range of 100 to 125mg/dl (i.e. 5.6 to 6.9mmol/l), especially greater than 110mg/dL and less than 126mg/dl (7.00mmol/L) disease.The fasting glucose concentration of " normal fasting glucose " individuality, less than 100mg/dl, is i.e. less than 5.6mmol/l。
It is big that term " glucose tolerance reduction " or " IGT " are defined as individuality 2 hours blood glucoses or serum glucose concentration after the meal In 140mg/dl (7.78mmol/L) and the disease less than 200mg/dL (11.11mmol/L).Abnormal glucose tolerance (is i.e. eaten Rear 2 hours blood glucoses or serum glucose concentration) can be to absorb after empty stomach after 75g glucose 2 hours, the Portugal of every deciliter of blood plasma The blood sugar content of grape sugar milligram number is measured.2 hours blood glucoses or the serum glucose after the meal that " normal glucose-tolerant " is individual Concentration is less than 140mg/dl (7.78mmol/L).
Term " hyperinsulinemia " is defined as having insulin resistant and blood glucose is normal or the sky of the abnormal individuality of blood glucose Abdomen or post-prandial serum or plasma insulin concentrations are higher than without insulin resistant and waist-to-hipratio < 1.0 (male) or < 0.8 (women's) The disease of normal thin individuality.
Term " insulin sensitivity ", " insulin resistant improvement " or " insulin resistant reduction " synonym and be used interchangeably.
Term " insulin resistant " is defined as wherein needing circulating insulin content and exceedes stimulate glucose normal anti- Should be to keep the state (Ford ES et al., JAMA. (2002) 287:356-9) of euglycemia state.Measure insulin resistant Method is euglycemia-hyperinsulinemia clamp procedure (euglycaemic-hyperinsulinaemic clamp test).The ratio of insulin and glucose is measured in combination insulin-glucose infusion technical scope.If glucose absorption Less than research background colony of institute 25%, then it is assumed that there is insulin resistant (WHO definition).More much easier than clamp procedure it is So-called mini model (minimal model), wherein during intravenous glucose tolerance test, under Fixed Time Interval Measure the insulin in blood and concentration of glucose, and thus calculate insulin resistant.Liver islets of langerhans can not be distinguished in this approach Element opposing and peripheral insulin resistance.
Additionally, can by the evaluation steady-state model of the insulin resistant " evaluation (HOMA-IR) " score (insulin resistant can By instruction) come quantitative insulin opposing (i.e. have the Patients with Insulin Resistance reaction to therapy), insulin sensitivity and high islets of langerhans Element mass formed by blood stasis (KatsukIA et al., Diabetes Care 2001；24:362-5).Reference is also made to measure insulin sensitivity The method (Matthews et al., Diabetologia 1985,28:412-19) of HOMA index, mensuration the Intact Islets former and pancreas of element Island element ratio method (Forst et al., Diabetes 2003,52 (supplementary issue 1): A459) and euglycemia clamp research.This Outward, Plasma adiponectin (adiponectin) content can be monitored with may substituting of insulin sensitivity.Calculate steady with following formula State Evaluation model (HOMA)-IR score estimation (Galvin P et al., the Diabet Med 1992 to insulin resistant；9:921- 8):
HOMA-IR=[Diagnostic Value of Fasting Serum insulin (μ U/mL)] × [fasting plasma glucose (mmol/L)/22.5]
Generally, clinical practice every day uses other parameter evaluating insulin resistant.Preferably, use such as patient's Triglyceride concentration, because the existence tool significant correlation of the increase of content of triglyceride and insulin resistant.
The patient of tool development IGT or IFG or type ii diabetes tendency has hyperinsulinemia for those and is defined as pancreas The normal person of blood glucose of insulin resistance.The typical patient with insulin resistant is the most overweight or fat.If can detect that insulin Opposing, then this is strength instruction pre-diabetes occur.Therefore, in order to keep glucose homeostasis, this individuality may need strong The insulin of health individuality 2-3 times, otherwise will cause any clinical symptoms.
The method of research Pancreatic beta cells function is supported with above for insulin sensitivity, hyperinsulinemia or insulin Anti-method is similar to: can be such as by measuring HOMA index (Matthews et al., the Diabetologia of β cell function 1985,28:412-19), the former ratio with insulin of Intact Islets element (Forst et al., Diabetes 2003,52 (supplementary issue 1): A459), insulin/C-peptide secretion after oral glucose tolerance test or meal tolerance test, or by using hyperglycemia to clamp Folder is studied and/or sets up mini model (Stumvoll et al., Eur J after the intravenous glucose tolerance test of frequently sampling Clin Invest 2001,31:380-81) measure the improvement of β cell function.
Term " pre-diabetes " is the individual disease tending to develop type ii diabetes.Pre-diabetes extends Fructus Vitis viniferae The definition that carbohydrate tolerance reduces so that it is include that there are fasting glucose (J.B.Meigs etc. within high normal range (>=100mg/dL) People, Diabetes 2003；52:1475-1484) and there is the individuality of on an empty stomach hyperinsulinemia (high plasma insulin concentrations). ADA (American Diabetes Association) and US National diabetes and digestion and nephropathy research Institute (National Institute of Diabetes and Digestive and Kidney Diseases) is sent out common The status report of entitled " the The Prevention or Delay of Type 2Diabetes " of cloth illustrates sugar futures before differentiating Urine disease is science and basic medical (the Diabetes Care 2002 of serious threat health；25:742-749).
The individuality being likely to be of insulin resistant is the individuality with two or more following characteristics: 1) overweight or fat, 2) hypertension, 3) hyperlipemia, 4) one or more first degree relatives diagnosis suffer from IGT or IFG or type ii diabetes.Can be by meter Calculate HOMA-IR score and determine the insulin resistant of these individualities.For purposes of the present invention, insulin resistant is defined as individuality HOMA-IR score > 4.0 or HOMA-IR scores carry out upper limits of normal defined in glucose and insulin analysis higher than laboratory Clinical disease.
Term " type ii diabetes " is defined as individual fasting glucose or serum glucose concentration more than 125mg/dL (6.94mmol/L) disease.The standard operation being measured as during general medical is analyzed of blood glucose value.If carrying out glucose tolerance examination Test, then the blood sugar content of diabetics will exceed on an empty stomach picked-up 75g glucose after 2 hours every deciliter of blood plasma 200mg Fructus Vitis viniferaes Sugar (11.1mmol/l).In glucose tolerance test, after empty stomach 10-12 hour, it is orally administered to 75g Fructus Vitis viniferae to patient to be measured Sugar, and will 1 hour and 2 hour record blood sugar contents before ingestion of glucose and after ingestion of glucose.In healthy individuals In, the blood sugar content before ingestion of glucose will be for every deciliter of blood plasma 60mg to 110mg, after ingestion of glucose 1 hour, will be less than 200mg/dL, and absorb latter 2 hours, will be less than 140mg/dL.If absorbing latter 2 hours, be worth for 140mg to 200mg, then this is regarded For abnormal glucose tolerance.
Term " late Type II diabetes " include Secondary cases (anti-diabetic) drug failure, tool insulin treatment indication and It is in progress into blood capillary and macrovascular complications (such as diabetic nephropathy or (type ii diabetes) patient of coronary heart disease (CHD).
Term " HbA1c " refers to the product of hemoglobin B chain nonenzymatic glycosylation.Those skilled in the art know it and survey Fixed.When monitoring the treatment of diabetes, HbA1c value is even more important.Because the generation of HbA1c be substantially dependent on blood sugar content and The erythrocytic life-span, so the average blood sugar content that HbA1c is all for 4-6 before reflecting in " blood glucose memory " meaning.HbA1c value is by sugar The sick intensive treatment well-tuned all the time of urine (i.e. less than sample total hemoglobin 6.5%) diabetics substantially better It is protected from diabetic microangiopathy.Such as, what the HbA1c value of diabetics was reached by metformin itself is flat All improve and be about 1.0-1.5%.In all diabeticss, this HbA1c value reduction is not enough to reach HbA1c < 6.5% and excellent Choosing < the required target zone of 6%.
In the scope of the invention, term " insufficient glycemic control " or " not enough glycemic control " refer to that patient shows HbA1c value higher than 6.5%, be especially more than 7.0%, even more higher than 7.5%, be especially more than 8% situation.
" metabolism syndrome ", also known as " X syndrome " (using in the case of dysbolismus), also known as " metabolism is bad combines Simulator sickness ", it is mainly characterized by syndrome (Laaksonen DE et al., the Am J Epidemiol 2002 of insulin resistant； 156:1070-7).According to ATP III/NCEP guilding principle (Executive Summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)JAMA:Journal of the American Medical Association(2001)285:2486- 2497), when there are three or more following risk factor, it is diagnosed as metabolism syndrome:
1. abdominal fatness, it is defined as male's waistline > 40 inches or 102cm, and women waistline > 35 inches or 94cm； Or for Japan race or Japanese patients, it is defined as male's waistline >=85cm and women waistline >=90cm；
2. triglyceride: >=150mg/dL
3. male HDL-cholesterol < 40mg/dL
4. blood pressure >=130/85mm Hg (SBP >=130 or DBP >=85)
5. fasting glucose >=110mg/dL or >=100mg/dL.
Have verified that NCEP defines (Laaksonen DE et al., Am J Epidemiol. (2002) 156:1070-7).Also may be used By in medical analysis and such as Thomas L (volume): " Labor und Diagnose ", TH-Books Standard method described in Verlagsgesellschaft mbH, Frankfurt/Main, 2000 measures the glycerol three in blood Ester and HDL cholesterol.
According to common definition, if shrinking pressure (SBP) more than 140mm Hg and diastolic pressure (DBP) more than 90mm Hg, then diagnose For hypertension.If patient suffers from overt diabetes (manifest diabetes), then it is presently recommended that shrink pressure and be brought down below 130mm Hg and diastolic pressure are brought down below the degree of 80mm Hg.
U.S. is followed in NODAT (diabetes of new outbreak after transplanting) and the definition of PTMS (metabolism syndrome after transplanting) closely Diabetes association of state (American Diabetes Association) is about the definition of type ii diabetes diagnostic criteria and the world Diabetic combinations meeting (International Diabetes Federation, IDF) and American Heart Association/American National heart Dirty, lung and Blood Research Institute (American Heart Association/National Heart, Lung, and Blood Institute) about the definition of metabolism syndrome.NODAT and/or PTMS and blood capillary and macrovascular diseases and event, transplanting The risk of repulsion, infection and death increases relevant.Differentiate the multiple potential risk factor relevant to NODAT and/or PTMS Predictor, including diabetes and immunosuppressant before Body Mass Index, transplanting before age higher when transplanting, male gender, transplanting.
Term " hyperuricemia " represents the disease of high serum total urate content.In human blood, American Medical Association (American Medical Association) thinks that 3.6mg/dL (about 214 μm ol/L) is to 8.3mg/dL (about 494 μm ol/ L) uric acid concentration is normal.High serum total urate content or hyperuricemia are the most relevant with multiple disease.Such as, high blood Clear total urate content can produce a class in joint and be referred to as the arthritis of gout.Gout is by the total uric acid of the high concentration in blood flow Formed produced by monosodium urate or uric acid crystal sick in the articular cartilage in joint, tendon and the surrounding tissue that salt content causes Disease.The inflammatory reaction of these tissues is excited in the formation urate of these tissues or uric acid.When uric acid or urate are in kidney During crystallization, in urine, the uric acid of saturated content may result in formation renal calculus.Additionally, high serum total urate content is generally with so-called Metabolism syndrome (including cardiovascular disease and hypertension) be correlated with.
Term " DPP-4 inhibitor " in the scope of the invention refers to live enzyme DPP IV (DPP-4) display suppression The compound of property.This inhibitory activity can be by IC50Value characterizes.IC shown by DPP-4 inhibitor50Value preferably shorter than 10000nM, Preferably shorter than 1000nM.Concrete IC shown by DPP-4 inhibitor50Value is less than 100nM, or even≤50nM.DPP-4 inhibitor IC50Value generally higher than 0.01nM, or even greater than 0.1nM.DPP-4 inhibitor can include biology and non-biological compound, especially Its non-peptide compound.The inhibitory action to DPP-4 can be measured, especially such as application WO 02/068420 by known in the literature method Or the method described in WO 2004/018468 (page 34) (being incorporated herein by reference)." DPP-4 suppresses term Agent " also comprise its pharmaceutically acceptable salt any, its hydrate and solvate, including crystal form out of the ordinary.
Term " is treated " and is comprised therapeutic treatment and the patient of this disease (especially dominant form) occurred.Therapeutic treatment can For alleviating the symptom treatment of the symptom of concrete indication, or reverse or partly reverse situation or the stopping of indication or slow down disease The cause of disease of progress processes.Therefore, the present composition and method can be used as the therapeutic treatment of such as a period of time and long-term Therapy.
Term " preventative process " and " prevention " are used interchangeably, and comprise and be in the wind developing disease mentioned above Patient in danger, thus reduce this risk.
Detailed Description Of The Invention
The aspect of the present invention, especially pharmaceutical composition, method and purposes, relate to the DPP-4 inhibitor of contextual definition, Two kinds and/or the third antidiabetic drug.In the inventive method and purposes, optionally give the second and optionally the third Antidiabetic drug, i.e. DPP-4 inhibitor combine the second and optionally the third antidiabetic drug give, or do not combine second Plant and optionally the third antidiabetic drug gives.In the inventive method and purposes, optionally give the third anti-diabetic Medicine, i.e. DPP-4 inhibitor and the second antidiabetic drug combine the third antidiabetic drug or do not combine the third anti-diabetic Medicine gives.
In first embodiment (embodiment A), DPP-4 inhibitor is following DPP-4 in the context of the present invention Any one in inhibitor:
Wherein R1 represents ([1,5] benzodiazine-2-base) methyl, (quinazoline-2-base) methyl, (quinoxalin-6-yl) first Base, (4-methyl-quinazoline-2-base) methyl, 2-Cyano-benzyl, (3-cyano-quinoline-2-base) methyl, (3-Cyano-pyridin- 2-yl) methyl, (4-methyl-pvrimidine-2-base) methyl or (4,6-dimethyl-pyrimidin-2-base) methyl, and R2 represents 3-(R)-ammonia Base-piperidin-1-yl, (2-amino-2-methyl-propyl group)-methylamino or (2-(S)-amino-propyl)-methylamino, or it can Pharmaceutical salts.
In the second embodiment (embodiment B), DPP-4 inhibitor is selected from following DPP-in the context of the present invention 4 inhibitor: sitagliptin, vildagliptin, BMS-477118, Egelieting,
(2S)-1-{ [2-(5-methyl-2-phenyl-Azoles-4-base)-ethylamino]-acetyl group }-pyrrolidine-2-formonitrile HCN,
(2S)-1-{ [1,1-dimethyl-3-(4-pyridin-3-yl-imidazoles-1-base)-propylcarbamic]-acetyl group }-pyrroles Alkane-2-formonitrile HCN,
(S)-1-((2S, 3S, 11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido [2,1-a] isoquinolin-3-base)-4-methyl fluoride-pyrrolidin-2-one,
(3,3-difluoropyrrolidin-1-base)-((2S, 4S)-4-(4-(pyrimidine-2-base) piperazine-1-base) pyrrolidin-2-yl) Ketone,
(1 ((3S, 4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-base)-1,3,5-triazine-2-base) pyrrolidine- 3-yl)-5,5-difluoropiperdin-2-ketone,
(2S, 4S)-1-{2-[(3S, 1R)-3-(1H-1,2,4-triazol-1-yl methyl) clopentylamino]-acetyl group }- 4-fluoropyrrolidine-2-formonitrile HCN,
(R)-2-[6-(3-amino-piperadine-1-base)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-Ji Jia Base] the fluoro-benzonitrile of-4-,
5-{ (S)-2-[2-((S)-2-cyano-pyrolidin-1-base)-2-oxo-ethylamino]-propyl group }-5-(1H-tetra- Azoles-5-base)-10,11-dihydro-5H-dibenzo [a, d] cycloheptatriene-2,8-dioctyl phthalate pair-dimethylformamide,
3-{ (2S, 4S)-4-[4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl Base } Thiazolidine,
[(2R)-1-{ [(3R)-pyrrolidin-3-yl amino] acetyl group } pyrrolidin-2-yl] boric acid,
(2S, 4S)-1-[2-[(4-ethoxy carbonyl bicyclo-[2.2.2] octyl-1-yl) amino] acetyl group]-4-fluorine pyrroles Alkane-2-formonitrile HCN,
2-({ 6-[(3R)-3-amino-3-methyl piperidine-1-base]-1,3-dimethyl-2,4-dioxo-1,2,3,4-four Hydrogen-5H-pyrrolo-[3,2-d] pyrimidine-5-base } methyl)-4-fluorobenzonitrile, and
6-[(3R)-3-amino-piperadine-1-base]-5-(the fluoro-benzyl of the chloro-5-of 2-)-1,3-dimethyl-1,5-dihydro-pyrrole And [3,2-d] pyrimidine-2,4-diketone,
Or its officinal salt.
About first embodiment (embodiment A), preferred DPP-4 inhibitor is any one in following compound Or whole and officinal salt:
1-[(4-methyl-quinazoline-2-base) methyl]-3-methyl-7-(2-butyne-1-base)-8-(3-(R)-amino- Piperidin-1-yl)-xanthine (with reference to WO 2004/018468, embodiment 2 (142)):
1-[([1,5] benzodiazine-2-base) methyl]-3-methyl-7-(2-butyne-1-base)-8-((R)-3-amino- Piperidin-1-yl)-xanthine (with reference to WO 2004/018468, embodiment 2 (252)):
1-[(quinazoline-2-base) methyl]-3-methyl-7-(2-butyne-1-base)-8-((R)-3-amino-piperadine-1- Base)-xanthine (with reference to WO 2004/018468, embodiment 2 (80)):
2-((R)-3-amino-piperadine-1-base)-3-(butyl-2-alkynyl)-5-(4-methyl-quinazoline-2-ylmethyl)- 3,5-dihydro-imidazols also [4,5-d] pyridazine-4-ketone (with reference to WO 2004/050658, embodiment 136):
1-[(4-methyl-quinazoline-2-base) methyl]-3-methyl-7-(2-butyne-1-base)-8-[(2-amino-2-first Base-propyl group)-methylamino]-xanthine (with reference to WO 2006/029769, embodiment 2 (1)):
1-[(3-cyano-quinoline-2-base) methyl]-3-methyl-7-(2-butyne-1-base)-8-((R)-3-amino-piperazine Pyridine-1-base)-xanthine (with reference to WO 2005/085246, embodiment 1 (30)):
1-(2-Cyano-benzyl)-3-methyl-7-(2-butyne-1-base)-8-((R)-3-amino-piperadine-1-base)-Huang Purine (with reference to WO 2005/085246, embodiment 1 (39)):
1-[(4-methyl-quinazoline-2-base) methyl]-3-methyl-7-(2-butyne-1-base)-8-[(S)-(2-amino- Propyl group)-methylamino]-xanthine (with reference to WO 2006/029769, embodiment 2 (4)):
1-[(3-Cyano-pyridin-2-base) methyl]-3-methyl-7-(2-butyne-1-base)-8-((R)-3-amino-piperazine Pyridine-1-base)-xanthine (with reference to WO 2005/085246, embodiment 1 (52)):
1-[(4-methyl-pvrimidine-2-base) methyl]-3-methyl-7-(2-butyne-1-base)-8-((R)-3-amino-piperazine Pyridine-1-base)-xanthine (with reference to WO 2005/085246, embodiment 1 (81)):
1-[(4,6-dimethyl-pyrimidin-2-base) methyl]-3-methyl-7-(2-butyne-1-base)-8-((R)-3-ammonia Base-piperidin-1-yl)-xanthine (with reference to WO 2005/085246, embodiment 1 (82)):
1-[(quinoxalin-6-yl) methyl]-3-methyl-7-(2-butyne-1-base)-8-((R)-3-amino-piperadine-1- Base)-xanthine (with reference to WO 2005/085246, embodiment 1 (83)):
In the above-mentioned DPP-4 inhibitor of embodiment of the present invention A, preferred DPP-4 inhibitor be 1-[(4-methyl- Quinazoline-2-base) methyl]-3-methyl-7-(2-butyne-1-base)-8-(3-(R)-amino-piperadine-1-base)-xanthine, especially It is its free alkali (it is also known as BI 1356 (linagliptin) or BI 1356).
As other DPP-4 inhibitor, it can be mentioned following compound:
-sitagliptin (sitagliptin, MK-0431), it has following structural formula A, and it is (3R)-3-amino-1- [3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-5H-[1,2,4] triazol [4,3-a] pyrazine-7-base]-4-(2,4,5-trifluoro-benzene Base) butyl-1-ketone, also known as (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro [1,2,4] triazol [4,3-a] pyrrole Piperazine-7 (8H)-yl]-1-(2,4,5-trifluorophenyl) butyl-2-amine,
In one embodiment, sitagliptin is the form of its dihydric phosphate, i.e. sitagliptin phosphate.At another In embodiment, sitagliptin phosphate is the form of crystal anhydrous compound or monohydrate.This type of embodiment refer to phosphoric acid west he Row spit of fland monohydrate.Januvia free base and officinal salt thereof are disclosed in United States Patent (USP) 6,699,871 and are disclosed in WO In the embodiment 7 of 03/004498.Crystalline sitagliptin monohydrate is disclosed in WO 2005/003135 and WO 2007/ In 050485.
It is thus possible, for instance about the details of preparation, preparation or using method about this compound or its salt, refer to these File.
The tablet formulation of sitagliptin can be with trade nameBuy.The tablet of sitagliptin/combination with metformin Preparation can be with trade nameBuy.
-vildagliptin (vildagliptin, LAF-237), it has following structural formula B, and it is (2S)-{ [(3-hydroxyl Diamantane (obsolete)-1-base) amino] acetyl group } pyrrolidine-2-formonitrile HCN, also known as (S)-1-[(3-hydroxyl-1-adamantyl) amino] second Acyl group-2-cyano-pyrolidin,
Vildagliptin is specifically disclosed in United States Patent (USP) 6,166,063 and is disclosed in the embodiment 1 of WO 00/34241. The concrete salt of vildagliptin is disclosed in WO 2007/019255.The crystal form of vildagliptin and vildagliptin tablet formulation It is disclosed in WO 2006/078593.Vildagliptin can be prepared as described in WO 00/34241 or WO 2005/067976.Improvement The vildagliptin preparation of release is disclosed in WO 2006/135723.
It is thus possible, for instance about the details of preparation, preparation or using method about this compound or its salt, refer to these File.
The tablet formulation expection of vildagliptin can be with trade nameBuy.Vildagliptin/combination with metformin Tablet formulation can be with trade nameBuy.
-BMS-477118 (saxagliptin, BMS-477118), it has following structural formula C, and it is (1S, 3S, 5S)-2- { (2S)-2-amino-2-(3-hydroxyadamantane-1-base) acetyl group }-2-azabicyclic [3.1.0] hexane-3-formonitrile HCN, also known as (S)-3-hydroxyadamantane glycine-L-cis-4,5-methylene pyrrolidine-2-formonitrile HCN (methanoprolinenitrile),
BMS-477118 is specifically disclosed in the embodiment 60 of United States Patent (USP) 6,395,767 and WO 01/68603.
In one embodiment, BMS-477118 is its HCl salt or its single benzoate form, such as WO 2004/052850 Disclosed in.In another embodiment, BMS-477118 is free alkali form.In another embodiment, BMS-477118 Monohydrate form in free alkali, as disclosed in WO 2004/052850.The HCl salt of BMS-477118 and the crystallization of free alkali Form is disclosed in WO 2008/131149.The method preparing BMS-477118 is also disclosed in WO 2005/106011 and WO 2005/ In 115982.BMS-477118 can formula in form of tablets, as described in WO 2005/117841.
It is thus possible, for instance about the details of preparation, preparation or using method about this compound or its salt, refer to these File.
-Egelieting (alogliptin, SYR-322), it has following structural formula E, and it is 2-({ 6-[(3R)-3-ammonia Phenylpiperidines-1-base]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-base } methyl) benzonitrile
Egelieting is specifically disclosed in US 2005/261271, EP 1586571 and WO 2005/095381.
In one embodiment, Egelieting is its benzoate, its hydrochlorate or the form of its toluene fulfonate, respectively As disclosed in WO 2007/035629.This type of embodiment refers to SYR-322.The polymorphic of SYR-322 It is disclosed in WO 2007/035372.The method of preparation Egelieting is disclosed in WO 2007/112368 and specifically disclosed at WO In 2007/035629.Egelieting (i.e. its benzoate) can be prepared in form of tablets and give, in WO 2007/033266 Described.The solid preparation of Egelieting/pioglitazone and preparation and purposes thereof are disclosed in WO 2008/093882.A Gelie The solid preparation of spit of fland/metformin and preparation and purposes thereof are disclosed in WO 2009/011451.
It is thus possible, for instance about the details of preparation, preparation or using method about this compound or its salt, refer to these File.
-(2S)-1-{ [2-(5-methyl-2-phenyl-Azoles-4-base)-ethylamino]-acetyl group }-pyrrolidine-2-formonitrile HCN Or its officinal salt, preferably mesylate, or
(2S)-1-{ [1,1-dimethyl-3-(4-pyridin-3-yl-imidazoles-1-base)-propylcarbamic]-acetyl group }-pyrroles Alkane-2-formonitrile HCN or its officinal salt:
These compounds and preparation method thereof are disclosed in WO 03/037327.
Mesylate and its crystalline polymorphs of previous compound are disclosed in WO 2006/100181.Latter compounds Fumarate and its crystalline polymorphs be disclosed in WO 2007/071576.These compounds can be with pharmaceutical compositions Preparation, as described in WO 2007/017423.
It is thus possible, for instance about the details of preparation, preparation or using method about these compound or its salts, refer to this A little files.
-(S)-1-((2S, 3S, 11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyridine And [2,1-a] isoquinolin-3-base)-4-methyl fluoride-pyrrolidin-2-one (also known as carmegliptin (carmegliptin)) or its Officinal salt:
This compound and preparation method thereof is disclosed in WO 2005/000848.Prepare this compound (especially its disalt Hydrochlorate) method be also disclosed in WO 2008/031749, WO 2008/031750 and WO 2008/055814.This compound can Prepare with pharmaceutical compositions, as described in WO 2007/017423.
It is thus possible, for instance about the details of preparation, preparation or using method about this compound or its salt, refer to these File.
-(3,3-difluoropyrrolidin-1-base)-((2S, 4S)-4-(4-(pyrimidine-2-base) piperazine-1-base) pyrrolidine-2- Base) ketone (also known as gosogliptin (gosogliptin)) or its officinal salt:
This compound and preparation method thereof is disclosed in WO 2005/116014 and US 7291618.
It is thus possible, for instance about the details of preparation, preparation or using method about this compound or its salt, refer to these File.
-(1 ((3S, 4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-base)-1,3,5-triazine-2-base) pyrrolidine- 3-yl)-5,5-difluoropiperdin-2-ketone or its officinal salt:
This compound and preparation method thereof is disclosed in WO 2007/148185 and US 20070299076.It is thus possible, for instance About the details of preparation, preparation or using method about this compound or its salt, refer to these files.
-(2S, 4S)-1-{2-[(3S, 1R)-3-(1H-1,2,4-triazol-1-yl methyl) clopentylamino]-acetyl group }- 4-fluoropyrrolidine-2-formonitrile HCN (also referred to as melogliptin (melogliptin)) or its officinal salt:
This compound and preparation method thereof is disclosed in WO 2006/040625 and WO 2008/001195.Specific requirement is protected The salt protected includes mesylate and tosilate.It is thus possible, for instance about about the preparation of this compound or its salt, preparation or The details of using method, refers to these files.
-(R)-2-[6-(3-amino-piperadine-1-base)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-base Methyl] the fluoro-benzonitrile of-4-or its officinal salt:
This compound and its production and use is disclosed in WO 2005/095381, US 2007060530, WO 2007/ 033350、WO 2007/035629、WO 2007/074884、WO 2007/112368、WO 2008/033851、WO 2008/ In 114800 and WO 2008/114807.Specifically claimed salt includes succinate (WO 2008/067465), benzoic acid Salt, benzene sulfonate, tosilate, (R)-mandelate and hydrochlorate.It is thus possible, for instance about this compound or its salt relevant The details of preparation, preparation or using method, refer to these files.
-5-{ (S)-2-[2-((S)-2-cyano-pyrolidin-1-base)-2-oxo-ethylamino]-propyl group }-5-(1H-tetra- Azoles-5-base)-10,11-dihydro-5H-dibenzo [a, d] cycloheptatriene-2,8-dioctyl phthalate is double-dimethylformamide or it is pharmaceutically acceptable Salt:
This compound and preparation method thereof is disclosed in WO 2006/116157 and US 2006/270701.It is thus possible, for instance About the details of preparation, preparation or using method about this compound or its salt, refer to these files.
-3-{ (2S, 4S)-4-[4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base] pyrrolidin-2-yl carbonyl Base } Thiazolidine (also known as teneligliptin (teneligliptin)) or its officinal salt:
This compound and preparation method thereof is disclosed in WO 02/14271.Concrete salt be disclosed in WO 2006/088129 and WO 2006/118127 (especially includes hydrochlorate, hydrobromate).The combination treatment using this compound is disclosed in WO In 2006/129785.It is thus possible, for instance about the details of preparation, preparation or using method about this compound or its salt, can join Examine these files.
-[(2R)-1-{ [(3R)-pyrrolidin-3-yl amino] acetyl group } pyrrolidin-2-yl] boric acid (also known as Du Gelie Spit of fland (dutogliptin)) or its officinal salt:
This compound and preparation method thereof is disclosed in WO 2005/047297, WO 2008/109681 and WO 2009/ In 009751.Concrete salt is disclosed in WO 2008/027273 (including citrate, tartrate).The preparation of this compound is public It is opened in WO 2008/144730.It is thus possible, for instance thin about preparation, preparation or the using method about this compound or its salt Joint, refers to these files.
-(2S, 4S)-1-[2-[(4-ethoxy carbonyl bicyclo-[2.2.2] octyl-1-yl) amino] acetyl group]-4-fluorine pyrroles Alkane-2-formonitrile HCN or its officinal salt:
This compound and preparation method thereof is disclosed in WO 2005/075421, US 2008/146818 and WO 2008/ In 114857.It is thus possible, for instance about the details of preparation, preparation or using method about this compound or its salt, refer to this A little files.
-2-({ 6-[(3R)-3-amino-3-methyl piperidine-1-base]-1,3-dimethyl-2,4-dioxo-1,2,3,4-four Hydrogen-5H-pyrrolo-[3,2-d] pyrimidine-5-base } methyl)-4-fluorobenzonitrile or its officinal salt, or 6-[(3R)-3-amino-piperazine Pyridine-1-base]-5-(the fluoro-benzyl of the chloro-5-of 2-)-1,3-dimethyl-1,5-dihydro-pyrrole also [3,2-d] pyrimidine-2,4-dione or Its officinal salt:
These compounds and preparation method thereof are disclosed in WO 2009/084497 and WO 2006/068163 respectively.Cause This, such as, about the details of preparation, preparation or using method about these compound or its salts, refer to these files.
Preferably, described DPP-4 inhibitor is selected from group G2, and it includes BI 1356, sitagliptin, vildagliptin, A Ge Arrange spit of fland, BMS-477118, carmegliptin, melogliptin, gosogliptin, teneligliptin and dutogliptin, or above-mentioned a kind of DPP-4 presses down The pharmaceutically acceptable salt of preparation, or its prodrug.
The concrete preferably DPP-4 inhibitor that the present invention is even more important is BI 1356." Li La as the term is employed herein Row spit of fland " refer to BI 1356 and pharmaceutically acceptable salt thereof, including its hydrate and solvate, and crystal form.Knot Crystalline form is described in WO 2007/128721.The method preparing BI 1356 is described in such as patent application WO 2004/ In 018468 and WO 2006/048427.The DPP-4 inhibitor that BI 1356 is suitable from structure is different, because it is in single treatment In method and/or when its second with the present invention and time optionally the third antidiabetic drug is applied in combination, merge special effect Can and long-acting and favourable pharmacological characteristics, receptor-selective and favourable side effect profile or produce unexpected controlling Treatment advantage or improvement.
For avoiding any query, the disclosure of aforementioned each document that above-cited and concrete DPP-4 inhibitor is relevant It is incorporated herein by reference with it.
In one aspect of the invention, the pharmaceutical composition of the present invention, method and purposes relate to comprising DPP-4 inhibitor As those compositionss of single-activity composition (there is not the second and the third antidiabetic drug) i.e. simultaneously, and/or, relate to It is used alone the monotherapy of DPP-4 inhibitor.
In another aspect of this invention, the pharmaceutical composition of the present invention, combination, method and purposes relate to comprising DPP-4 and press down Preparation and the second antidiabetic drug are as those compositionss of independent active component (the most there is not the third antidiabetic drug) Or combination, and/or, it is directed to use with the double combinations therapy of DPP-4 inhibitor and the second antidiabetic drug.
In another aspect of this invention, the pharmaceutical composition of the present invention, combination, method and purposes relate to comprising DPP-4 and press down The compositions of preparation, the second and the third antidiabetic drug or combination, and/or, it is directed to use with DPP-4 inhibitor, the second Triple combination treatments with the third antidiabetic drug.
It addition, the DPP-4 inhibitor of the present invention is further characterized in that described DPP-4 inhibitor significantly damages tool There is the glomerule of the type ii diabetes patient of chronic renal insufficiency (such as slight, moderate or severe renal impairment or latter stage nephropathy) And/or the function of renal tubules, and/or described DPP-4 inhibitor need not have chronic renal insufficiency (such as slight, in Degree or severe renal impairment or latter stage nephropathy) type ii diabetes patient in adjust dosage.
Described the second antidiabetic drug and (in the presence of) the third antidiabetic drug selected from group G3, it include biguanide, Thiazolidinedione, sulfonylureas, row how, alpha-glucosidase inhibitor, GLP-1 analog or its pharmaceutically acceptable salt.? The following discloses the preferred implementation about the second and/or the third antidiabetic drug.
Group G3 includes biguanide.The example of biguanide is metformin, phenformin and buformin.Preferably biguanide is that diformazan is double Guanidine.DPP-4 inhibitor combination biguanide, especially metformin, it is possible to provide more effectively glycemic control and/or can be together with biguanide Effect, such as, reduce body weight, and it has such as overall beneficial effect to generally the most relevant with type ii diabetes metabolism syndrome.
" metformin " refers to metformin or its pharmaceutically acceptable salt, such as hydrochloric acid as the term is employed herein Salt, metformin (2:1) fumarate and metformin (2:1) succinate, hydrobromate, parachlorophen-oxyacetic acid salt or double Hydroxynaphthoate (embonate), and other known unitary or the melbine salt of dicarboxylic acids.Metformin used herein is excellent Select Metformin.
G3 group comprises thiazolidinedione.The example of thiazolidinedione (TZD) is pioglitazone (pioglitazone) and sieve Lattice row ketone (rosiglitazone).TZD therapy increases to body weight and fat redistribution is relevant.Additionally, TZD causes fluid retention And disable in patients with congestive heart failure.Also increase relevant to risk of bone fracture with TZD long-term treatment.DPP-4 inhibitor combines Thiazolidinedione (especially pioglitazone) can provide more effective glycemic control side effect that TZD can be made to treat to be down to Little.
" pioglitazone " refers to pioglitazone as the term is employed herein, including its enantiomer, its mixture and Racemic modification, or its pharmaceutically acceptable salt, such as hydrochlorate.
" rosiglitazone " refers to rosiglitazone as the term is employed herein, including its enantiomer, its mixture and Racemic modification, or its pharmaceutically acceptable salt, such as maleate.
G3 group comprises sulfonylureas.The example of sulfonylureas is glibenclamide (glibenclamide), tolbutamide (tolbutamide), glimepiride (glimepiride), glipizide (glipizide), gliquidone (gliquidone), Glibornuride (glibornuride), glibenclamide (glyburide), glisoxepide (glisoxepide) and gliclazide (gliclazide).Preferably sulfonylureas is tolbutamide, gliquidone, glibenclamide and glimepiride, especially Ge Lieben Urea and glimepiride.Because effect of sulfonylureas exhausts with therapeutic process, so the combination of DPP-4 inhibitor and sulfonylureas is just More preferably can provide extra benefit to patient for glycemic control.Equally, with sulphonylurea therapy, generally and body weight is with treating Journey and be gradually increased relevant, and DPP-4 inhibitor reduces the ability of body weight and this side effect for the treatment of of sulfonylureas can be made to be down to Little and/or improve metabolism syndrome.And, hyperglycemia can be down to minimum with the combination of sulfonylureas by DPP-4 inhibitor, and its Another unwanted side effect for sulfonylureas.This combination also makes to reduce the dosage of sulfonylureas, and it can also result in lighter low blood Sugar disease.
As used herein group's " glibenclamide ", " glimepiride ", " gliquidone ", " glibornuride ", " gliclazide ", Each term of " glisoxepide ", " tolbutamide " and " glipizide " refers to active medicine out of the ordinary or it is pharmaceutically acceptable Salt.
How G3 group comprises row.Arranging example how is Nateglinide (nateglinide), repaglinide (repaglinide) And Mitiglinide (mitiglinide).Because its effect exhausts with therapeutic process, so DPP-4 inhibitor and meglitinide (meglitinide) combination can provide extra benefit to patient for more preferably glycemic control.Equally, with meglitinide Treatment is generally gradually increased relevant with body weight with therapeutic process, and DPP-4 can make this side effect for the treatment of of meglitinide be down to Minimum and/or improve metabolism syndrome.And, hyperglycemia can be down to minimum with the combination of meglitinide by DPP-4 inhibitor, And another unwanted side effect that it is meglitinide.This combination also makes to reduce the dosage of meglitinide, and it can also result in Lighter hypoglycemia.
" Nateglinide " refers to Nateglinide as the term is employed herein, including its enantiomer, its mixture and Racemic modification, or its pharmaceutically acceptable salt and ester.
" repaglinide " refers to repaglinide as the term is employed herein, including its enantiomer, its mixture and Racemic modification, or its pharmaceutically acceptable salt and ester.
G3 group comprises alpha-glucosidase inhibitor.The example of alpha-glucosidase inhibitor is acarbose (acarbose), voglibose (voglibose) and miglitol (miglitol).DPP-4 inhibitor and alpha-glucosaccharase The additional benefit of the combination of enzyme inhibitor may with such as under the individual drugs of relatively low-dose more effective glycemic control relevant, And/or reduce the unwanted the intestines and stomach side effect of alpha-glucosidase inhibitor.
Each term of group " acarbose ", " voglibose " and " miglitol " refers to activity out of the ordinary as used herein Medicine or its pharmaceutically acceptable salt.
G3 group comprises the inhibitor of GLP-1 analog.The example of GLP-1 analog is Exenatide (exenatide), profit Draw Shandong peptide (liraglutide), taspoglutide (taspoglutide), semaglutide (semaglutide), albiglutide And lixisenatide (lixisenatide) (albiglutide).The combination of DPP-4 inhibitor and GLP-1 analog can be such as Good glycemic control is realized under the relatively low-dose of individual drugs.Additionally, the ability that GLP-1 analog reduces body weight can be with DPP- The character of 4 inhibitor acts on the most jointly.On the other hand, when the GLP-1 analog of low dosage combines DPP-4 inhibitor, Side effect (such as feel sick, gastrointestinal side effect is such as vomitted) can be reduced.
Group " Exenatide ", " Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] ", " taspoglutide ", " semaglutide ", " albiglutide " as used herein Each term of " lixisenatide " refers to active medicine out of the ordinary or its pharmaceutically acceptable salt.
In an embodiment (embodiment E1), pharmaceutical composition of the present invention, combination, method and purposes relate to wherein DPP-4 inhibitor and the second antidiabetic drug are preferably selected from the combination of table 1.
Table 1
In detailed description of the invention (embodiment E2), pharmaceutical composition of the present invention, combination, method and purposes relate to wherein DPP-4 inhibitor is the combination of BI 1356.According to embodiment E2, described the second antidiabetic drug is preferably selected from table 2.
Table 2
Embodiment The second antidiabetic drug
E2.1 Selected from group G3
E2.2 Metformin
E2.3 Pioglitazone
E2.4 Rosiglitazone
E2.5 Glibenclamide
E2.6 Glimepiride
E2.7 Gliquidone
E2.8 Nateglinide
E2.9 Repaglinide
E2.10 Acarbose
E2.11 Voglibose
E2.12 Miglitol
E2.13 Exenatide
E2.14 Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37]
E2.15 Taspoglutide
E2.16 Semaglutide
E2.17 Albiglutide
E2.18 Lixisenatide
(such as diformazan is double with the monotherapy using independent DPP-4 inhibitor or the second or the third antidiabetic drug Guanidine monotherapy) or use the second to compare with the dual therapy of the third antidiabetic drug, DPP-4 inhibitor and the second with And the combination of optionally the third antidiabetic drug can improve glycemic control, the most hereinafter described glycemic control of patient.Additionally, With use DPP-4 inhibitor and one of the second or the third antidiabetic drug or use the second and the third antidiabetic drug Combination treatment compare, three recombinations of DPP-4 inhibitor and the second and the third antidiabetic drug can improve glycemic control, The most hereinafter described glycemic control of patient.Glycemic control improvement is defined as blood glucose and reduces increase and HbA1c minimizing increase.For Monotherapy in patient (patient the most hereinafter described), by give can not be further higher than the medicine of specific maximum dose level Significantly improve glycemic control.Additionally, in view of potential side effect, it may be undesirable to life-time service maximum dose level is treated.Therefore, By using the monotherapy of DPP-4 inhibitor or one of the second or the third antidiabetic drug can not reach in all patients To gratifying glycemic control.When monotherapy can not obtain complete glycemic control, dual therapy is likely to become necessary.Very To only using two kinds of combination treatments selected from DPP-4 inhibitor and the second and the medicines of the third antidiabetic drug can't be All patients produce complete glycemic control and/or the complete glycemic control of long-term generation.When dual therapy can not obtain complete blood When sugar controls, triple therapies are likely to become necessary.In the patient that these glycemic control are not enough, diabetes may continue to progress and It is likely to occur the complication relevant with diabetes, such as macrovascular complications.With monotherapy or use one or both respectively The dual therapy of composition of medicine (combination partner) is compared, the pharmaceutical composition of the present invention or combination and this Bright method makes the HbA1c value of more patient be reduced to required target zone, such as < 7% and preferred < 6.5%, and therapeutic treatment Time is longer, such as in the case of dual or triple combination treatments.
Additionally, the combination of DPP-4 inhibitor of the present invention and the second and optionally the third therapeutic agent allows to reduce DPP-4 inhibitor or the second or the third antidiabetic drug or the dosage of even two or three active ingredient.Decrease in dose To benefits subjects, otherwise it can suffer from using the side effect, especially of the therapy of one or more active ingredients of higher dosage The side effect that the second and/or the third antidiabetic drug cause.Therefore, drug regimen and the inventive method of the present invention can Show less side effect, therefore make therapy more tolerant to and improve the compliance of patient for treatment.
The DPP-4 inhibitor of the present invention (through increased activity GLP-1 content) can reduce the secretion of glucagon in patient. Therefore, this will limit the generation of hepatic glucose.It addition, the active GLP-1 content of the rising produced by DPP-4 inhibitor is by right β cell regeneration and new life have beneficial effect.All these features of DPP-4 inhibitor can make the present invention pharmaceutical composition or Combination or method is particularly useful and treatment on relevant.
When the present invention mentions the patient needing treatment or prevention, its treatment referring mainly to people and prevention, but drug regimen Thing also can be applied in the veterinary of mammal mutually.In the scope of the invention, adult patient preferred age be 18 years old or more than People.Same in the scope of the invention, patient be teenager, i.e. age be 10 to less than 18 years old, preferred age be 13 to being less than The people of 18 years old.
In an embodiment of the invention, treatment or the prevention of the present invention is suitable to need the trouble of this treatment or prevention Person, these patients have one or more after diagnosing selected from following disease: overweight and obesity, especially I level obesity, II level Obesity, III level obesity, visceral obesity and abdominal fatness.Additionally, the treatment of the present invention or prevention are advantageously adapted to prohibit Avoid the patient that body weight increases.Such as owing to giving the second and/or the third antidiabetic drug, therapy any puts on weight Therefore effect may weaken or even eliminate.
In another embodiment of the present invention, pharmaceutical composition or the combination of the present invention shows splendid glycemic control merit Effect, is especially reducing fasting plasma glucose, Post-prandial plasma glucose and/or glycosylated hemoglobin (HbA1c) aspect.Pass through Giving pharmaceutical composition or the combination of the present invention, accessible HbA1c reduces equal to or more than preferably 1.0%, is more preferably equal to Or more than 2.0%, even more preferably equal to or more than 3.0%, and reduce especially in the range of 1.0% to 3.0%.
Additionally, the method for the present invention and/or purposes can be used for, display is a kind of, the patient of the following disease of two or more:
A () fasting glucose or serum glucose concentration are more than 110mg/dL or more than 100mg/dL, especially greater than 125mg/ dL；
B () Post-prandial plasma glucose equals to or more than 140mg/dL；
C () HbA1c value equals to or more than 6.5%, especially equal to or more than 7.0%, especially equal to or more than 7.5%, very To more specifically equal to or more than 8.0%.
Invention additionally discloses pharmaceutical composition or combination suffering from type ii diabetes for improvement or showing pre-diabetes Purposes in the glycemic control of the patient of the first symptom.Therefore, present invention additionally comprises diabetes mellitus prevention.Therefore, if above-mentioned one Kind of pre-diabetes symptom i.e. uses the pharmaceutical composition of the present invention or combination to improve glycemic control after occurring, then can postpone or in advance Anti-dominant type ii diabetes outbreak.
Additionally, the pharmaceutical composition of the present invention or combination are particularly suited for treating the patient with insulin-dependent, i.e. warp Insulin or insulin derivates or insulin substitution thing or comprise insulin or derivatives thereof or the preparation for treating of substitute or To treat through it or need its patient treated.These patients include type ii diabetes patient and type i diabetes patient.
Therefore, according to an embodiment of the invention, it is provided that improve glycemic control and/or reduction in the patient needed Fasting plasma glucose, Post-prandial plasma glucose and/or the method for glycosylated hemoglobin HbA1c, described patient suffers from after diagnosing Glucose tolerance reduces (IGT), impaired fasting glucose (IFG), insulin resistant, metabolism syndrome and/or II type or I type glycosuria Sick, it is characterised in that the DPP-4 inhibitor of contextual definition and optionally the second and optionally the third anti-diabetic Medicine such as gives patient with combination.
According to another embodiment of the present invention, it is provided that as the improvement type ii diabetes of diet and the supplementary means of motion The method of the glycemic control of patient, especially adult patient.
Unless otherwise indicated, the patient in implication the most of the present invention can include patient and/or the medicine not accepting Drug therapy The patient that thing is treated in advance, such as, use one or more traditional oral and/or the patient of parenteral antidiabetic medicine treatment. Therefore, unless otherwise indicated, the combination treatment in implication the most of the present invention can include initial combination treatment, substitute and/or add Combination treatment.
Can find, the pharmaceutical composition of the application of the invention or combination, even (outstanding the patient that glycemic control is insufficient Although it has carried out the combined therapy of the second or the third antidiabetic drug or the second and the third antidiabetic drug, such as Although the metformin carrying out maximum tolerated dose is administered orally the group of single therapy or metformin and the third antidiabetic drug Close treatment) the middle improvement obtaining glycemic control.
It is therefore found that the application of the invention pharmaceutical composition or combination, although maximum tolerance agent can accepted Metformin, thiazolidinedione (such as pioglitazone) or the oral monotherapy of sulfonylureas of amount, or metformin and sulphonyl Urea, metformin and thiazolidinedione (such as pioglitazone), or the mouth of thiazolidinedione (such as pioglitazone) and sulfonylureas Take combination treatment, but the most insufficient patient of glycemic control obtains the improvement of glycemic control.
It has also been found that the combination of the application of the invention, although can especially suppress with DPP-4 inhibitor or DPP-4 The combined therapy of agent and the second or the third antidiabetic drug is (although such as accepting the DPP-4 inhibitor of maximum tolerated dose Oral monotherapy or DPP-4 inhibitor and the second or the double combinations of the third antidiabetic drug), but glycemic control is still Insufficient patient obtains the glycemic control of improvement.
The maximum tolerated dose of metformin is such as 2000mg/ days, 1500mg/ days (such as in Asian countries) or 850mg, three times a day or any equivalent dose.The maximum tolerated dose of sitagliptin is such as 100mg, once a day or any Equivalent dose.
Therefore, the method for the present invention and/or purposes can be used for that display is a kind of, the patient of the following disease of two or more:
A () uses independent diet and motion and glycemic control is insufficient；
Although b () has carried out the oral monotherapy of metformin, although the most carrying out the diformazan of maximum tolerated dose The oral monotherapy of biguanide, but glycemic control is the most insufficient；
Although c () has carried out the oral monotherapy of the second or the third antidiabetic drug, although the most having carried out The second of big tolerance dose or the oral monotherapy of the third antidiabetic drug, but glycemic control is the most insufficient；
Although d () has carried out the combination treatment of two kinds of medicines in the second and the third antidiabetic drug, but blood Sugar controls the most insufficient；
Although e () has carried out the oral monotherapy of thiazolidinedione, although the most carrying out the thiophene of maximum tolerated dose The oral monotherapy of oxazolidinedione (such as pioglitazone), but glycemic control is the most insufficient；
Although f () has carried out the oral monotherapy of sulfonylureas, although the most carrying out the sulfonylureas of maximum tolerated dose Oral monotherapy, but glycemic control is the most insufficient；
Although g () has carried out two kinds of medicines in metformin, thiazolidinedione (such as pioglitazone) and sulfonylureas The combination treatment of thing is (although the most having carried out selected from metformin/pioglitazone, metformin/sulfonylureas and sulfonylureas/pyrrole lattice The combination treatment of the double combinations of row ketone), but glycemic control is the most insufficient.
The method of the present invention and/or purposes can be additionally used in show one or more following diseases patient:
Although h () has carried out insulin (such as with or be not accompanied by other conventional oral antidiabetic thing) treatment, But glycemic control is the most insufficient.
Although i () has carried out the combination treatment of insulin and the second and/or the third antidiabetic drug, although the most Carry out insulin and the metformin of maximum tolerated dose, thiazolidinedione (such as pioglitazone) or the combination treatment of sulfonylureas Although (the most having carried out the double combinations selected from metformin/insulin, sulfonylureas/insulin and pioglitazone/insulin Combination treatment) treatment, but glycemic control is the most insufficient.
Dual or three recombinations, method and/or the purposes of the present invention can be additionally used in that show disease (j) or (k) respectively A little patients:
Although j () has carried out the oral monotherapy of DPP-4 inhibitor, although the most having carried out maximum tolerated dose The oral monotherapy of DPP-4 inhibitor, but glycemic control is the most insufficient；
Although k () has carried out the Oral compositions therapy of DPP-4 inhibitor and the second or the third antidiabetic drug, especially Although carrying out the dual oral therapy of at least one composition of medicine of maximum tolerated dose, but glycemic control being the most insufficient.
In an embodiment of the invention, pharmaceutical composition or combination are suitable to treat and suffer from one or more after diagnosing The patient of following disease:
-insulin resistant,
-hyperinsulinemia,
-pre-diabetes,
-type ii diabetes, especially late Type II diabetes,
-type i diabetes.
Additionally, the pharmaceutical composition of the present invention or combination are particularly suited for treating suffers from one or more following diseases after diagnosing Patient:
(a) obesity (including I level, II level and/or III level obesity), visceral obesity and/or abdominal fatness,
(b) triglyceride blood content >=150mg/dL,
(c) female patient HDL-cholesterol blood level < 40mg/dL and male patient < 50mg/dL,
D () shrinks pressure >=130mm Hg and diastolic pressure >=85mm Hg,
(e) fasting glucose content >=110mg/dL or >=100mg/dL.
Think that suffering from glucose tolerance after diagnosing reduces (IGT), impaired fasting glucose (IFG), insulin resistant and/or generation Thank to patient evolution's cardiovascular disease (such as myocardial infarction, coronary heart disease, cardiac dysfunction, thromboembolic events) of syndrome Risk increases.The glycemic control of the present invention can make cardiovascular risk reduce.
Additionally, the pharmaceutical composition of the present invention and method are particularly suited for the patient after treating organs is transplanted, especially diagnose tool There is a patient of one or more following diseases:
A () age is higher, be especially more than 50 years old,
(b) male gender,
C () is overweight, obesity (including I level, II level and/or III level obesity), visceral obesity and/or abdominal obesity Disease,
D () transplants front diabetes,
(e) immunosuppressive therapy.
The pharmaceutical composition of the present invention or combination, especially due to DPP-4 inhibitor therein, show good safety Situation.Therefore, treatment or the prevention of the present invention is possibly used for taboo and uses the list of another antidiabetic drug (such as metformin) The patient that one therapy and/or these medicines to therapeutic dose do not tolerate.The treatment of the present invention or prevention are especially to display one Multiple following disease or there is the patient of one or more following diseases that risk increases may be favourable: renal insufficiency or kidney Disease, heart disease, heart failure, hepatopathy, pneumonopathy, the catabolism state (catabolytic state) of lactic acidosis and/ Or dangerous or period of pregnancy or breast-feeding female patient.
In addition, it is possible to find give the pharmaceutical composition of the present invention or combine without hypoglycemia risk or hypoglycemia risk Low.Therefore, treatment or the prevention of the present invention are also favourable to the patient of display hypoglycemia or the risk increase suffering from hypoglycemia.
The pharmaceutical composition of the present invention or combination are particularly suited at type ii diabetes patient's Long-term therapy or prevention upper and lower Disease described in literary composition and/or disease, be particularly suited for its long-term blood glucose and control.
Term " for a long time " as used by context represents to be treated patient or is longer than 12 weeks to the time that patient is administered, excellent Choosing is longer than 25 weeks, is even more preferably longer than 1 year.
Therefore, a specific embodiment of the present invention provides and improves (for a long time improve) type ii diabetes patient, outstanding Its late Type II diabetes patient, suffer from overweight, obesity the most after diagnosing and (include that I level, II level and/or III level are fat Disease), the Therapeutic Method (preferred oral therapy) of the glycemic control of the patient of visceral obesity and/or abdominal fatness.
When DPP-4 inhibitor and the second and optionally give (such as with single system together with the third antidiabetic drug Agent or give with two or three independent preparations simultaneously) time and/or when it alternately gives (such as independent with two or three Preparation gives successively) time, all observe above-mentioned effect.
In the present invention, it should be understood that the purposes combining or combining is considered respectively (separate), successively (sequential), simultaneously (simultaneous), parallel (concurrent), intersect in chronological order Give composition (chronologically staggered) or alternately (alternate).It is to be understood that described DPP-4 suppresses Agent and other active substance described can be administered in different dosage form in single dosage form or respectively.
In this article, the present invention contains interior " combination " or " combination " and also includes but not limited to fixing and revocable shape Formula and purposes.
Should be appreciated that the drug regimen being intended to give and need in present invention treatment or prevention the present invention used to patient The amount of thing is by with route of administration, the character of the disease needing treatment or prevention and the order of severity, patient age, body weight and health shape Condition, concomitant drugs and change, and the most at last by resident doctor (attendant physician) determine.It is however generally that, DPP-4 inhibitor of the present invention included in pharmaceutical composition, combination or dosage form and optionally the second and/or optionally the The amount of three kinds of antidiabetic drugs be enough to when giving improve the glycemic control of patient to be treated.
Disclose the pharmaceutical composition of the present invention and the inventive method and purposes to be used DPP-4 inhibitor, second The preferred scope of the amount of kind and/or the third antidiabetic drug.These scopes refer to that (the most such as body weight is about with regard to adult patient The people of 70kg) for every day the amount that gives and can be according to giving every day 2,3,4 times or more than 4 times and other route of administration and patient Age is adjusted accordingly.The scope of dosage and amount calculates for indivedual active parts.Used in the combination treatment of the present invention Indivedual DPP-4 inhibitor, and/or indivedual the second and/or the dosage preferably less than monotherapy of the third antidiabetic drug or Know the dosage used in therapy, thus avoid possible toxicity that those medicines are used as to cause during monotherapy and bad pair Effect.
Within the scope of the present invention, pharmaceutical composition or combination preferred oral give.Other form of medication is likely to and describes Below.One or more dosage forms comprising DPP-4 inhibitor and/or the second and/or the third antidiabetic drug are preferred For peroral dosage form or the dosage form that is generally known.
It is said that in general, the amount of the DPP-4 inhibitor of the combination of the present invention, combination, method and combined use is preferably typically In the range of the 1/5 to 1/1 of the amount using the monotherapy of this DPP-4 inhibitor to recommend.
When being orally administered to, the preferred dose scope of BI 1356 is 0.5mg to 10mg every day, and preferably 2.5mg every day is extremely 10mg, most preferably 1mg to 5mg every day.The preferred scope of the amount in pharmaceutical composition is 0.5 to 10mg, especially 1 to 5mg.Specifically The example of dosage strengths is 1,2.5,5 or 10mg.The using of active ingredient can carry out up to 3 times every day, the most 1 or 2 times per day. Those preparations that suitably BI 1356 preparation is disclosed in can being application WO 2007/128724, the disclosure of this application will It is incorporated herein by reference.
The typical doses specification of the double combinations of BI 1356/metformin is 2.5/500mg, 2.5/850mg and 2.5/ 1000mg, it can give 1-3 time every day, preferably every day twice.
When being orally administered to, the preferred dose scope of sitagliptin is 10 to 200mg every day, especially 25 to 150mg every day.West The recommended dose of Ta Lieting is calculated as 100mg or twice 50mg every day once a day with active part (free alkali anhydride).Medicine The preferred scope of the amount in compositions is 10 to 150mg, is especially 25 to 100mg.Example is 25,50,75 or 100mg.Live The using of sexual element can carry out up to 3 times every day, the most 1 or 2 times per day.The salt of sitagliptin, especially phosphoric acid can be calculated accordingly The equivalent of salt monohydrate.Patients with renal failure is preferably used the sitagliptin adjusting dosage, such as 25 and 50mg.Xi Talie The typical doses specification of the double combinations of spit of fland/metformin is 50/500mg and 50/1000mg.
When being orally administered to, the preferred dose scope of vildagliptin is 10 to 150mg every day, especially 25 to 150mg every day, 25 To 100mg or 25 to 50mg or 50 to 100mg.Such as, being given daily of vildagliptin is 50 or 100mg.Pharmaceutical composition In the preferred scope of amount be 10 to 150mg, especially 25 to 100mg.Example is 25,50,75 or 100mg.Executing of active ingredient With carrying out up to 3 times every day, the most 1 or 2 times per day.The typical doses specification of the double combinations of vildagliptin/metformin For 50/850mg and 50/1000mg.
When being orally administered to, the preferred dose scope of Egelieting is 5 to 250mg every day, especially 10 to 150mg every day.Medicine The preferred scope of the amount in compositions is 5 to 150mg, especially 10 to 100mg.Example be 10,12.5,20,25,50,75 and 100mg.The using of active ingredient can carry out up to 3 times every day, the most 1 or 2 times per day.
When being orally administered to, the preferred dose scope of BMS-477118 is 2.5 to 100mg every day, especially 2.5 to 50mg every day. The preferred scope of the amount in pharmaceutical composition is 2.5 to 100mg, especially 2.5 to 50mg.Example is 2.5,5,10,15,20,30, 40,50 and 100mg.The using of active ingredient can carry out up to 3 times every day, the most 1 or 2 times per day.BMS-477118/metformin The typical doses specification of double combinations be 2.5/500mg and 2.5/1000mg.
When being orally administered to, the preferred dose scope of dutogliptin is 50 to 400mg every day, especially 100 to 400mg every day. The preferred scope of the amount in pharmaceutical composition is 50 to 400mg.Example is 50,100,200,300 and 400mg.Active ingredient Use and can carry out up to 3 times every day, the most 1 or 2 times per day.
The detailed description of the invention of DPP-4 inhibitor of the present invention relates to those DPP-4 inhibitor of oral administration, and it is at low dose Amount level is effective for treatment, such as every patient every day < 100mg or < 70mg, preferably < 50mg, more preferably < 30mg or < (when needing, being divided into 1 to 4 single dose, preferably 1 or 2 single dose, it can be for 20mg, even more preferably 1mg to 10mg Formed objects), the dosage level of especially 1mg to 5mg (more particularly 5mg), it is preferable that oral administration once a day, more excellent Selection of land in one day whenever, with or be not accompanied by food and be administered.It is therefoie, for example, the BI 1356 of daily oral dose 5mg can To give with dosage regimen once a day, (i.e. 5mg BI 1356 gives (i.e. once a day) or with twice dosage regimen every day 2.5mg BI 1356, every day twice), in one day whenever, with or be not accompanied by food and be administered.
It is said that in general, the second in the combination of the present invention, combined method and combined use and/or the third anti-diabetic The amount of medicine is preferably in the range of the 1/5 to 1/1 of the amount being generally directed to use the monotherapy of this antidiabetic drug to recommend.Use low Indivedual the second of dosage and/or the third antidiabetic drug in monotherapy can be avoided or minimize when those medicines are used as The possible toxicity caused during monotherapy and adverse side effect.
When being orally administered to, the preferred dose scope of metformin be 250 to 3000mg every day, especially every day 500 to 2000mg.The preferred scope of the amount in pharmaceutical composition should be mutually 250 to 1000mg, especially 500 to 1000mg or 250 to 850mg.Example is 500,750,850 or 1000mg.The giving the most once a day of this tittle, every day twice or every day three Secondary.Such as, the amount of 500,750 and 850mg preferably needs once a day, every day twice or be administered three times a day, and 1000mg Amount preferably needs once a day or twice administration every day.Some controlled-or sustained-release preparation allows to be administered once a day.Diformazan Biguanide can be such as in trade mark GLUCOPHAGETM、GLUCOPHAGE-DTMOr GLUCOPHAGE-XRTMSale form give.
When being orally administered to, the preferred dose scope of pioglitazone is 5 to 50mg every day.Amount in pharmaceutical composition preferred Scope is respectively 5 to 50mg, 10 to 45mg and 15 to 45mg accordingly.Example is 15,30 or 45mg.Giving preferably of this tittle Once a day or every day twice, it is especially once a day.Pioglitazone can be in such as trade mark ACTOSTMSale form give.
When being orally administered to, the preferred dose scope of rosiglitazone is 1mg to 10mg every day.Amount in pharmaceutical composition excellent Selecting scope is 1 to 10mg, 2 to 8mg, 4 to 8mg and 1 to 4mg.Example is 1,2,4 or 8mg.This tittle give preferably every day Once or every day twice.Dosage preferably should be less than 8mg every day.Rosiglitazone can be in such as trade mark AVANDIATMSale shape Formula gives.
When being orally administered to, the preferred dose of thiazolidinedione (in addition to pioglitazone as described above or rosiglitazone) Scope is 2 to 100mg every day.Be administered once per day for the treatment of, the preferred scope of the amount of pharmaceutical composition twice or thrice be respectively 2 to 100mg, 1 to 50mg and 1 to 33mg.
When being orally administered to, the preferred dose scope of glibenclamide is 0.5 to 15mg every day, especially 1 to 10mg every day.Medicine The preferred scope of the amount in compositions is 0.5 to 5mg, especially 1 to 4mg.Example is 1.0,1.75 and 3.5mg.Giving of this tittle Give the most once a day, every day twice or three times a day.Glibenclamide can be in such as trade mark EUGLUCONTMSale form Give.
When being orally administered to, the preferred dose scope of glimepiride is 0.5 to 10mg every day, especially 1 to 6mg every day.Medicine The preferred scope of the amount in compositions is 0.5 to 10mg, especially 1 to 6mg.Example is 1,2,3,4 and 6mg.Giving of this tittle Be preferably the most once a day, every day twice or three times a day, the most once a day.Glimepiride can be in such as trade mark AMARYLTM Sale form give.
When being orally administered to, the preferred dose scope of gliquidone is 5 to 150mg every day, especially 15 to 120mg every day.Medicine The preferred scope of the amount in compositions is 5 to 120mg, especially 5 to 30mg.Example is 10,20,30mg.Giving of this tittle Be preferably the most once a day, every day twice, three times a day or four times a day.Gliquidone can be in such as trade mark GLURENORMTM's Sale form gives.
When being orally administered to, the preferred dose scope of glibornuride is 5 to 75mg every day.Amount in pharmaceutical composition preferred Scope is 5 to 75mg, especially 10 to 50mg.The giving the most once a day of this tittle, every day twice or three times a day.
When being orally administered to, the preferred dose scope of gliclazide is 20 to 300mg every day, especially 40 to 240mg every day.Medicine The preferred scope of the amount in compositions is 20 to 240mg, especially 20 to 80mg.Example is 20,30,40 and 50mg.This tittle Give the most once a day, every day twice or three times a day.
When being orally administered to, the preferred dose scope of glisoxepide is 1 to 20mg every day, especially 1 to 16mg every day.Medicine group The preferred scope of the amount in compound is 1 to 8mg, especially 1 to 4mg.The giving the most once a day of this tittle, every day twice, Three times a day or four times a day.
When being orally administered to, the preferred dose scope of tolbutamide be 100 to 3000mg every day, preferably every day 500 to 2000mg.The preferred scope of the amount in pharmaceutical composition is 100 to 1000mg.Giving the most once a day or often of this tittle Day twice.
When being orally administered to, the preferred dose scope of glipizide is 1 to 50mg every day, especially 2.5 to 40mg every day.Every day The preferred scope of the amount giving pharmaceutical composition once, twice or thrice be respectively 1 to 50mg, 0.5 to 25mg and 0.3 to 17mg。
When being orally administered to, the preferred dose scope of Nateglinide is 30 to 500mg every day, especially 60 to 360mg every day.Medicine The preferred scope of the amount in compositions is 30 to 120mg.Example is 30,60 and 120mg.This tittle give preferably every day Once, every day twice or three times a day.Nateglinide can be in such as trade mark STARLIXTMSale form give.
When being orally administered to, the preferred dose scope of repaglinide is 0.1 to 16mg every day, especially 0.5 to 6mg every day.Medicine The preferred scope of the amount in compositions is 0.5 to 4mg.Example is 0.5,1,2 or 4mg.This tittle give preferably every day Once, every day twice, three times a day or four times a day.Repaglinide can be in such as trade mark NOVONORMTMSale form give Give.
When being orally administered to, the preferred dose scope of acarbose is 50 to 1000mg every day, especially 50 to 600mg every day. The preferred scope of the amount in pharmaceutical composition is 50 to 150mg.Example is 50 and 100mg.This tittle give preferably every day Once, every day twice, three times a day or four times a day.Acarbose can be in such as trade mark GlucobayTMSale form give Give.
When being orally administered to, the preferred dose scope of voglibose be 100 to 1000mg every day, especially every day 200 to 600mg.The preferred scope of the amount in pharmaceutical composition is 50 to 300mg.Example is 50,100,150,200 and 300mg.These The giving the most once a day of amount, every day twice, three times a day or four times a day.Voglibose can be in such as trade mark BasenTMOr VoglisanTMSale form give.
When being orally administered to, the preferred dose scope of miglitol is 25 to 500mg every day, especially 25 to 300mg every day.Medicine The preferred scope of the amount in compositions is 25 to 100mg.Example is 25,50 and 100mg.This tittle give preferably every day Once, every day twice, three times a day or four times a day.Miglitol can be in such as trade mark GlysetTMSale form give.
The preferred dose scope of GLP-1 analog (especially Exenatide) is μ g every day 5 to 30, especially μ g every day 5 to 20. The preferred scope of the amount in pharmaceutical composition is 5 to 10 μ g.Example is 5 and 10 μ g.The giving the most once a day of this tittle, Every day twice, three times a day or four times a day subcutaneous injection.Exenatide can be in such as trade mark ByettaTMSale form give Give.Durative action preparation (being preferred for weekly subcutaneous injection) comprises the Ai Sai of the amount of 0.1 to 3.0mg, preferably 0.5 to 2.0mg That peptide.Example is 0.8mg and 2.0mg.The example of Exenatide durative action preparation is Byetta LARTM。
The preferred dose scope of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] is 0.5 to 3mg every day, especially 0.5 to 2mg every day.In pharmaceutical composition The preferred scope of amount is 0.5 to 2mg.Example is 0.6,1.2 and 1.8mg.Giving the most once a day or every day of this tittle Twice subcutaneous injection.
DPP-4 inhibitor in the pharmaceutical composition of the present invention and the inventive method and purposes and the second and/or the 3rd Plant the amount of therapeutic agent corresponding to dosage range out of the ordinary provided above.Such as, the pharmaceutical composition of the present invention, combination, method and Preferred dose scope in purposes be the amount of 0.5 to 10mg (especially 1 to 5mg, especially 2.5mg or 5mg) BI 1356 and/or The metformin of the amount of 250 to 1000mg (especially 500mg, 850mg or 1000mg).Preferably every day is orally administered to once or two Secondary.
In the purposes of combined method of the present invention and combination, described DPP-4 inhibitor and described the second and/or the third Therapeutic combination is administered, and includes but not limited to that described active component is administered simultaneously, and the most simultaneously, or described activity becomes Point alternating delivery, i.e. gives the first or two kinds of active component and gives other two kinds over time or a kind of activity becomes Point, in i.e. three kinds active component, at least two is administered successively.Described a period of time can be 30 minutes to 12 hours.Combine or replace Administration can once a day, twice, three times or four times, the most once-or twice-a-day.
About giving of DPP-4 inhibitor and the second and/or the third antidiabetic drug, all three active ingredient can Be present in single dosage form, such as in one tablet or capsule, or one or both active ingredients may be present in separate dosage forms, Such as in two similar and different dosage forms.
About alternately giving, one or two kind of active ingredient be present in separate dosage forms, such as two similar and different dosage forms In.
Therefore, the drug regimen of the present invention can exist with single dosage form, its comprise DPP-4 inhibitor and the second and Optionally the third antidiabetic drug.Or, the drug regimen of the present invention can exist with two separate dosage forms, one of them agent Type comprises DPP-4 inhibitor and another dosage form comprises the second and adds optionally the third antidiabetic drug, or at three recombinations In the case of, dosage form comprises DPP-4 inhibitor and adds the one in the second or the third antidiabetic drug and another dosage form is divided Do not comprise the third or the second antidiabetic drug.Or, in the case of three recombinations, drug regimen of the present invention can be with three Individual separate dosage forms exists, one of them dosage form comprises DPP-4 inhibitor and second dosage form comprise the second antidiabetic drug and 3rd dosage form comprises the third antidiabetic drug.Or, in the case of double combinations, drug regimen of the present invention can be with two Individual dosage form respectively exists, and one of them dosage form comprises DPP-4 inhibitor and second dosage form comprises the second antidiabetic drug.
When a kind of active ingredient more frequently must give (such as than another active ingredient (such as needing to give once a day) Every day twice) time be likely to occur this situation.Therefore, " combination gives " also includes first combining and gives all active ingredients, and one Being given only the administration time-histories of a kind of active ingredient after the section time again, vice versa.
Therefore, present invention additionally comprises the drug regimen in separate dosage forms, one of them dosage form comprises DPP-4 inhibitor and Two kinds and/or optionally the 3rd therapeutic agent, and another dosage form only comprises the second and/or optionally the 3rd therapeutic agent.
Therefore, present invention additionally comprises for difference, successively, simultaneously, parallel, alternately or in chronological order cross-reference activity The pharmaceutical composition of composition or combination.
In out of the ordinary or multiple dosage forms, preferably pharmaceutical composition in test kit be applicable to combination treatment, with full neatly The individualized treatment of foot patient needs.
According to the first embodiment, preferred test kit comprises:
(a) first container, it contains the dosage form comprising DPP-4 inhibitor and at least one pharmaceutically acceptable carrier, And
B () second container, it contains and comprises the second antidiabetic drug and at least one pharmaceutically acceptable carrier Dosage form, and optionally
C () the 3rd container, it contains and comprises the third antidiabetic drug and at least one pharmaceutically acceptable carrier Dosage form.
According to the second embodiment, preferred test kit comprises:
(a) first container, its contain comprise DPP-4 inhibitor and the second or the third antidiabetic drug and at least one The dosage form of pharmaceutically acceptable carrier, and
B () second container, it contains and comprises the third or the second antidiabetic drug and at least one is pharmaceutically acceptable The dosage form of carrier.
According to the 3rd embodiment, preferred test kit comprises:
(a) first container, it contains the dosage form comprising DPP-4 inhibitor and at least one pharmaceutically acceptable carrier, And
B () second container, it contains and comprises the second and the third antidiabetic drug and at least one is pharmaceutically acceptable The dosage form of carrier.
Another aspect of the invention is a kind of goods, its drug regimen in separate dosage forms comprising the present invention and label or Package insert, this label or package insert comprise the explanation that separate dosage forms gives with combination.
According to the first embodiment, goods comprise (a) and comprise the pharmaceutical composition of DPP-4 inhibitor of the present invention；And (b) mark Sign or package insert, it include described medicine can or will with the explanation that give of combination, such as with comprise the second of the present invention The drug regimen of kind of antidiabetic drug, or with the consolidating of the second antidiabetic drug comprising the present invention and the third antidiabetic drug Fixed or independent assortment (such as medicine) combines.
According to the second embodiment, goods comprise the second antidiabetic drug and (b) label or medicine that (a) comprise the present invention Product description, it includes the explanation that described medicine can or will give with combination, such as with the DPP-4 inhibitor comprising the present invention Drug regimen, or with comprise the fixing or independent assortment of the DPP-4 inhibitor of the present invention and the third antidiabetic drug (such as Medicine) combination.
According to the 3rd embodiment, goods comprise (a) and comprise DPP-4 inhibitor of the present invention and the second antidiabetic drug Pharmaceutical composition and (b) label or package insert, it includes the explanation that described medicine can or will give with combination, such as with Comprise the drug regimen of the third antidiabetic drug of the present invention.
The required dosage of the pharmaceutical composition of the present invention is easily to provide once a day or with dividing that appropriate intervals gives Secondary dosage (such as every day twice, three times or more than three times dosage) provides.
Pharmaceutical composition can be through formula in liquid or solid form or in being suitable to give by sucking or be blown into Form is oral, per rectum, per nasal, locally (include buccal and Sublingual), percutaneous, transvaginal or parenteral (include intramuscular, subcutaneous And intravenous) give.Preferred oral gives.If suitable, then preparation is preferably in discontinuous dosage device, and can be by ripe in drug world Prepared by any method known.All methods all comprise the following steps: make active ingredient pharmaceutically acceptable with one or more Carrier (as liquid-carrier or Fine-powdered solids carrier or both) combine, and to make product shaping the most in due course be required system Agent.
Pharmaceutical composition can be in the form of through formula: tablet, granule, fine grained agent, powder, capsule, Caplet, soft Capsule, pill, oral administration solution, syrup, dry syrup, chewable tablet, coated tablet, effervescent tablet, drop, suspension, rapidly dissolving tablet, oral fast Speed dispersible tablet etc..
Pharmaceutical composition and dosage form preferably comprise one or more pharmaceutically acceptable carriers.Preferred vector is necessary " can Accept ", it is meant that compatible with other composition of preparation and harmless to its receiver.The example of pharmaceutically acceptable carrier is Known to those skilled in the art.
The pharmaceutical composition being suitable to be orally administered to is preferably in discontinuous unit form, such as capsule, including respectively containing scheduled volume The Perle of active ingredient, cachet or tablet；Powder or granule；Solution, suspension or emulsion, such as syrup, Elixir or self emulsifying transmission system (SEDDS).Active ingredient also can in bolus (bolus), electuary (electuary) or stick with paste Agent form.Can be containing knowing excipient, such as binding agent, filler, lubricant, disintegrate for the tablet being orally administered to and capsule Agent or wetting agent.Can be according to the method coated tablet known in technique.Oral liquid can be in the form of, such as water Property or oily suspensions, solution, emulsion, syrup or elixir；Maybe can be in restoring with water or other suitable medium before use Dry products.These liquid preparations can be containing knowing additive, and (it can include food for such as suspending agent, emulsifying agent, Non-aqueous vehicles With oil) or preservative.
The pharmaceutical composition of the present invention also can (such as be noted by injection, such as rapid intravenous for parenteral by formula Penetrate or continuous infusion), and can be in adding in the ampoule of preservative, pre-filled syringe, small size infusion or multi-dose container Unit dosage forms.The form of suspension, solution or emulsion that compositions can use such as in oiliness or aqueous media and can containing Such as suspending agent, stabilizer and/or the formula agent of dispersant.Or, active ingredient can in by aseptic separation sterile solid or By the powder form obtained from solution lyophilizing, it reconstructs with suitable medium (the most aseptic apirogen water) before use.
Carrier is the pharmaceutical composition the being suitable to rectally most preferably suppository form in unit dose of solid.Suitably Carrier includes cocoa butter and other material usually used in this field, and suppository preferably pass through mixed active compound and softening or Melted carrier, cools down subsequently and shapes formation in a mold.
For the medical applications in warm-blooded vertebrate (the particularly mankind), the compounds of this invention generally with 0.001-100mg/kg body weight, preferably use with the dosage of 0.1-15mg/kg, use 1-4 time every day in each case.Go out In this purpose, carrier that optionally can be conventional with one or more inertia with the compound of other active substance combination and/or dilute Release agent to mix together, such as with corn starch, lactose, glucose, microcrystalline Cellulose, magnesium stearate, polyvinylpyrrolidone, lemon Lemon acid, tartaric acid, water, water/ethanol, water/glycerol, water/Sorbitol, water/Polyethylene Glycol, propylene glycol, cetyl stearyl alcohol, Carboxymethyl cellulose or fatty material (such as, tallow) or its appropriate mixture are incorporated into the galenical (example of routine together As, element sheet or coated tablet, capsule, powder, suspension or suppository) in.
Therefore, the pharmaceutical composition of the present invention comprising DPP-4 inhibitor as defined herein is used such as this by technical staff Described in field prepared by pharmaceutically useful formulation excipients.The example of these excipient includes but not limited to diluent, binding agent, load Body, filler, lubricant, flow improver additive, crystallization delayer, disintegrating agent, solubilizing agent, coloring agent, pH adjusting agent, surface activity Agent and emulsifying agent.
Example for the suitable diluents of embodiment A compound includes cellulose powder, calcium hydrogen phosphate, red algae sugar Alcohol, low substituted hydroxypropyl cellulose, mannitol, pregelatinized starch or xylitol.In these diluent, mannitol, Low substituted hydroxypropyl cellulose and pregelatinized starch are even more important.
Example for the Suitable lubricants of embodiment A compound includes Pulvis Talci, Polyethylene Glycol, behenic acid calcium, hard Fat acid calcium, castor oil hydrogenated or magnesium stearate.In these lubricants, magnesium stearate is even more important.
Example for the suitable binders of embodiment A compound include copolyvidone (vinyl pyrrolidone and its The copolymer of its ethenyl derivatives), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidine Alkanone (polyvidone), pregelatinized starch, or low substituted hydroxypropyl cellulose (L-HPC).In these binding agents, copolyvidone It is even more important with pregelatinized starch.
Example for the suitable disintegrants of embodiment A compound includes corn starch or crospovidone.Collapse at these Solving in agent, corn starch is even more important.
The proper method of the pharmaceutical preparation of the DPP-4 inhibitor of preparation embodiment of the present invention A is:
● will be the active substance direct compression of mixture of powders form with appropriate tablet excipient；
● pelletize by proper excipient, mix with proper excipient subsequently, subsequently tabletting and film coating；Or
● mixture of powders or granule packaging are become capsule.
Suitable method of granulating is:
● wet granulation in forced mixer, passes through fluid bed drying subsequently；
● an autoclave pelletizes (one-pot granulation)；
● fluidized bed granulation；Or
● with proper excipient dry granulation (such as, being suppressed by cylinder) and tabletting or be packaged into capsule subsequently.
The exemplary composition of the DPP-4 inhibitor of embodiment of the present invention A comprises the first diluent mannitol, has The pregelatinized starch as the second diluent of additional adhesives characteristic, binding agent polyvidone, disintegrating agent corn starch, Yi Jizuo For the magnesium stearate of lubricant, wherein polyvidone and/or corn starch are optional.
About dosage form, preparation and the administration details of DPP-4 inhibitor of the present invention, refer to scientific literature and/or disclosed Patent document, particularly those files cited herein.
These pharmaceutical compositions (or preparation) can be packed in many ways.Normally, for the object of distribution (article for distribution) includes the container comprising pharmaceutical composition with appropriate form.Tablet typical case be packaged in easily In processing, distribute and in the suitable outer package that preserves, and during preserving with environment Long contact time time guarantee fitting of compositions Work as stability.The outer package of tablet can be bottle or blister package.
Such as comprising pharmaceutical composition or the suitable bottle of combination of the DPP-4 inhibitor of embodiment of the present invention A Can be made up of glass or polymer (optimization polypropylene (PP) or high density polyethylene (HDPE) (HD-PE)), and seal with screw-cap.Spiral Cap can provide Childproof safety seal (child resistant safety closure) (such as by pressure seal mouth press- And-twist closure), it is used for preventing or stop child getting in contact content.If desired (such as in high humility area), it is provided that Additionally use desiccant (such as bentonite, molecular sieve or preferably silica gel), the shelf life of the compositions of packaging can be extended.
The such as suitable bubble of the pharmaceutical composition or combination for comprising the DPP-4 inhibitor of embodiment of the present invention A Cover packaging includes pushing up paper tinsel (top foil) (it can be torn by tablet) and bottom (it includes the pocket for tablet), or by its group Become.Top paper tinsel includes tinsel, and particularly (such as having 20 μm to 45 μm, preferably 20 μm are to 25 μm for aluminium foil or aluminium alloy paillon foil Thickness), and within it (sealed sides) is coated with by heat seal polymer layer.Bottom can include with Vingon (PVDC) bag The multiple layer polymer paillon foil (such as polrvinyl chloride (PVC)) covered；Or with the PVC paillon foil of polytrifluorochloroethylene (PCTFE) laminate layer or Multiple layer polymer-metal-polymer paillon foil (PVC/ aluminum-polyamide compositions of (cold-formable) laminate layer of such as cold forming Thing).
Object may also include label or package insert, and it is with reference in the commercial packaging being typically included in treatment product Description, it can comprise indication, usage, consumption, administration, contraindication and/or use the points for attention etc. of this treatment product to believe Breath.In one embodiment, label or package insert point out that said composition can be used for any purpose as herein described.
Pharmaceutical composition and the method for the present invention show favourable in treating and preventing those described above disease and disease Effect.Compared with the monotherapy of active component, double combinations shows favourable effect.With the one in three kinds of active component Or the dual therapy of two kinds compares, three recombinations show favourable effect.Favourable effect is found in such as effectiveness, dosage Specification, administration frequency, pharmacodynamic properties, pharmacokinetic property, less side effect, convenience, compliance etc..
About BI 1356, synthetic method is known to the art and as described in document, especially such as WO 2002/ 068420, described in WO 2004/018468 or WO 2006/048427, disclosures of these documents is incorporated herein.Tool The polymorph crystals deformation of body DPP-4 inhibitor and preparation are disclosed in WO 2007/128721 and WO 2007/128724 respectively In, disclosures of these documents is incorporated herein by reference.Concrete DPP-4 inhibitor and metformin or other combination medicine The preparation of thing is disclosed in WO 2009/121945, the disclosure of which is incorporated herein.
The synthetic method of other DPP-4 inhibitor is described in scientific literature and/or disclosed patent documentation, the most above In the document quoted.
Active ingredient, especially DPP-4 inhibitor and/or the second and/or the third antidiabetic drug, can be in pharmaceutically may be used The salt form accepted.Pharmaceutically acceptable salt includes, but is not limited to the salt of such as mineral acid, this mineral acid example hydrochloric acid, sulphuric acid And phosphoric acid；The salt of organic carboxyl acid, this organic carboxyl acid such as oxalic acid, acetic acid, citric acid, malic acid, benzoic acid, maleic acid, fumaric acid, Tartaric acid, succinic acid and glutamic acid, and the salt of organic sulfonic acid, this organic sulfonic acid such as Loprazolam and p-methyl benzenesulfonic acid.Can pass through The compound mixing appropriate amount and ratio in solvent and distintegrant forms salt with acid.It is carried out also by with other salt form Cation or anion exchange obtain.
Active ingredient or its pharmaceutically acceptable salt can be in such as hydrates or alcohol adducts (alcohol adduct) Solvate form thereof.
Can be by any of above active substance, combination and the side in the animal model as known in the art test scope of the invention Method.In the following, it is described that the pharmacology being suitable to assess DPP-4 inhibitor, pharmaceutical composition, combination and the method for the present invention is correlated with The experiment in vivo of characteristic:
Such as db/db mice, ob/ob mice, Zucker Fatty (fa/fa) rat or Zucker Diabetic The hereditary hyperinsulinemia of Fatty (ZDF) rat or diabetic animal are tested the DPP-4 inhibitor of the present invention, medicine Compositions, combination and method.Additionally, it can be such as the HanWistar through streptozotocin (streptozotocin) pretreatment Or the animal of the experiment induced Diabetic of Sprague Dawley rat is tested.
Can give individually and the DPP-4 inhibitor of combination and the second and optionally the third antidiabetic drug at single After, animal model mentioned above is tested in oral glucose tolerance test the present invention combination effect to glycemic control. After carrying out oral glucose stimulation (glucose challenge) in overnight fasting animal, the time-histories of follow-up investigation blood glucose. As peak glucose concentration reduces or glucose AUC reduces measured, with each monotherapy or three kinds of active ingredients of use respectively In the double combinations therapy of combination of two kinds compare, present invention combination can significantly improve glucose oscillation.Additionally, in institute above State the DPP-4 inhibitor and the second repeatedly given in animal model alone or in combination and optionally the third antidiabetic drug Afterwards, can be by measuring the effect to glycemic control of the HbA1c pH-value determination pH in blood.With each monotherapy or double combinations therapy (using the combination of two kinds in three kinds of active ingredients the most respectively) is compared, and present invention combination can significantly reduce HbA1c.
Can by mentioned earlier in animal model the combination of relatively low-dose and monotherapy or double combinations therapy to blood glucose control The effect of system, tests decrease in dose possible in one or more DPP-4 inhibitor, the second and the third antidiabetic drug. Compared with placebo treatment, the present invention of relatively low-dose combines and can significantly improve glycemic control, and the monotherapy of relatively low-dose Or double combinations therapy respectively is the most invalid.
Can be come by the active GLP-1 content in the blood plasma on an empty stomach or measuring animal model mentioned above under Postprandial The increase of these content that the treatment of the present invention causes after determining single or multiple administration.Equally, can measure under the same conditions The reduction of glucagon content in blood plasma.
Can increase or by pancreas by measuring insulin content in animal model mentioned above after multiple dosing The β cell quality increased is measured or by measuring in separated islets of langerhans by morphological analysis after partial immunity histochemical stain The insulin secretion that the glucose increased stimulates determine DPP-4 inhibitor of the present invention individually and with the second and optionally The combination of the third antidiabetic drug is to β cell regeneration and the excellent effect of new life.
Owing to different metabolic function disease occurs the most simultaneously, therefore it is frequently necessary to make multiple different activities composition mutually group Close.Therefore, depending on the function disease diagnosed, if making DPP-4 inhibitor and the active substance group being conventionally used for each disease Closing, can obtain improved therapeutic outcome, these active substances be that such as one or more are selected from other anti-diabetic material Active substance, especially reduce HDL concentration in Blood Glucose concentration or lipid concentration, elevating blood, reduce blood pressure or treat Active substance needed for atherosclerosis or obesity.
Above-mentioned DPP-4 inhibitor also can be used in combination with other active substance in addition to it is for single therapy, can obtain whereby Obtain improved therapeutic outcome.This combined therapy can as the independent assortment of these materials or with fixed Combination (such as with tablet Or capsule) form give.Can buy with pharmaceutical composition for the pharmaceutical preparation of combination and compatibility medicine needed for this or can pass through Technical staff uses the method for routine to carry out formula.Many local in prior art of the active substance can buied with pharmaceutical composition All it is described, " the Rote of such as federal association of the pharmaceutical industry" in the annual medicine catalogue published, or the annual manufacturer's information assemble about prescription drugs updated (compilation of manufacturers ' information on prescription drugs) (referred to as " doctor's case Head reference " and (Physician ' s Desk Reference)) in.
The example of anti-diabetic composition of medicine is metformin；Sulfonylurea, such as glibenclamide, tolbutamide, lattice The U.S. urea of row, glipizide, gliquidone, glibornuride and gliclazide；Nateglinide；Repaglinide；Thiazolidinediones, example Such as rosiglitazone and pioglitazone；PPAR gamma modulators, such as Mei Tageliesheng (metaglidase)；PPAR-gamma agonist, Such as GI 262570；PPAR-γ antagonist；PPAR-γ/alpha modulators, such as Ge Liezha (tesaglitazar), Mo Geta Azoles (muraglitazar), aleglitazar (aleglitazar) and indeglitazar, AVE0897 and KRP297；PPAR- γ/α/δ regulator；AMPK-activator, such as AICAR；Acetyl-CoA carboxylase (ACC1 and ACC2) inhibitor；Two acyls are sweet Oil-acetyltransferase (DGAT) inhibitor；Pancreatic beta cell GCRP agonist, such as SMT3-receptor-agonist and GPR119； 11 β-HSD-inhibitor；FGF19 agonist or the like；Alpha-glucosidase inhibitor, such as acarbose, voglibose And miglitol；α 2-antagonist；Insulin and insulin analog, such as insulin human, insulin lispro, paddy rely insulin (insulin glusilin), r-DNA-insulin aspart (insulin aspart), NPH insulin, insulin detemir, zinc pancreas Island element suspension and insulin Glargine (insulin glargin)；Gastric inhibitory polypeptide (GIP)；White dextrin and white dextrin analog (example Such as Pramlintide or Da Walin peptide (davalintide))；Or GLP-1 and GLP-1 analog, such as Exendin-4, such as end Fill in that peptide (exenatide), Exenatide LAR, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37]
(liraglutide), taspoglutide (taspoglutide), lixisenatide (AVE-0010), LY-2428757 (gather The GLP-1 of PEGylation), LY-2189265 (being connected to the GLP-1 analog of IgG4-Fc heavy chain), semaglutide Or albiglutide (albiglutide) (semaglutide)；SGLT2-inhibitor, such as Da Gelie are clean (dapagliflozin), She Gelie clean (sergliflozin) (KGT-1251), A Gelie clean (atigliflozin) or bank lattice Clean (canagliflozin) or (the 1S)-1,5-of row is dehydrated-1-[3-(1-benzothiophene-2-ylmethyl)-4-fluorophenyl]-D-mountain Pears alcohol；The inhibitor (such as, trodusquemine) of Protein-tyrosine-phosphatase；The inhibitor of G-6-Pase；Really Sugar-1,6-bisphosphatase regulator；Glycogen phosphorylase regulator；Glucagon receptor antagonist；Phosphoenolpyruvate Carboxylic kinases (PEPCK) inhibitor；Pyruvic dehydrogenase kinase (PDK) inhibitor；(50mg is extremely for tyrosine kinase inhibitor 600mg), such as PDGF-receptor-kinases (sees, EP-A-564409, WO 98/35958, US 5093330, WO 2004/ 005281 and WO 2006/041976)；Glucokinase/regulation protein modulators, including glucokinase activating agents；Glycogensynthase Inhibitors of kinases；Inhibitor containing SH2 domain inositol 5-phosphatase 2 type (SHIP2)；IKK inhibitor, such as high dose water Poplar acid esters；JNK1 inhibitor；Protein kinase C-theta inhibitors；β 3 agonist, such as Li Tuobeilong (ritobegron), YM 178, Suo Labeilong (solabegron), Ta Libeilong (talibegron), N-5984, GRC-1087, Lei Fabeilong (rafabegron)、FMP825；Aldose reductase inhibitor, such as AS 3201, zenarestat, fidarestat, epalrestat, So Ni Sita (ranirestat), NZ-314, CP-744809 and CT-112；SGLT-1 or SGLT-2 inhibitor；KV1.3 passage Inhibitor；GPR40 regulator；SCD-1 inhibitor；CCR-2 antagonist；Dopamine-receptor stimulant (bromocriptine methanesulfonate (bromocriptine mesylate)[Cycloset])；Deacetylase stimulant and other DPP-4 inhibitor.
Metformin is generally up to the dosage of change in 2500mg/ days with about 500mg to 2000mg, uses about 100mg extremely 500mg's or 200mg to 850mg (every day 1-3 time) or about 300mg to 1000mg (once-or twice-a-day) is various to prescription Case gives, or with about 100mg to 1000mg or preferably 500mg to 1000mg (once-or twice-a-day) or about 500mg extremely The dosage of 2000mg (once a day) gives SRM.Concrete dosage strengths can be 250,500,625,750,850 and 1000mg metformin hydrochloride.
For the child of 10 to 16 years old, the recommendation initial dose of metformin was 500mg, once a day.If this dosage Sufficient result can not be obtained, then increase dosage to 500mg, every day twice.The increment of 500mg can be increased weekly further to The daily dosage of big 2000mg, divides and gives (such as 2 or 3 times dosage) several times.Metformin can be administered with food, to reduce Feel sick.
The dosage of pioglitazone is typically about 1-10mg, 15mg, 30mg or 45mg, once a day.
Rosiglitazone generally gives with 4mg to 8mg dosage, and (or being divided into twice), (typical doses specification was 2,4 once a day And 8mg).
Glibenclamide generally gives with the dosage of 2.5-5 to 20mg, once a day (or being divided into twice) (typical doses specification It is 1.25,2.5 and 5mg), or Micronized Glyburide gives with the dosage of 0.75-3 to 12mg, once a day (or it is divided into two Secondary) (typical doses specification is 1.5,3,4.5 and 6mg).
Glipizide is generally administered once per day for the treatment of (or up to 40mg, at twice) (typical case with the dosage of 2.5 to 10-20mg Dosage strengths is 5mg and 10mg), or extend release glipizide be administered once per day for the treatment of with the dosage of 5-10mg (up to 20mg) (typical doses specification is 2.5,5 and 10mg).
Glimepiride generally gives with the dosage of 1-2 to 4mg (up to 8mg), and (typical doses specification is 1,2 once a day And 4mg).
Glibenclamide/metformin double combinations thing is generally with 1.25/250mg (once a day) to 10/1000mg (every day Twice) dosage give (typical doses specification is 1.25/250,2.5/500 and 5/500mg).
Glipizide/metformin double combinations generally gives with the dosage of 2.5/250 to 10/1000mg, every day twice (typical doses specification is 2.5/250,2.5/500 and 5/500mg).
Glimepiride/metformin double combinations generally gives with the dosage of 1/250 to 4/1000mg, every day twice.
Rosiglitazone/glimepiride double combinations is generally with 4/1mg (once-or twice-a-day) to 4/2mg (every day twice) Dosage give (typical doses specification is 4/1,4/2,4/4,8/2 and 8/4mg).
Pioglitazone/glimepiride double combinations generally gives (typical case with the dosage of 30/2 to 30/4mg (once a day) Dosage strengths is 30/4 and 45/4mg).
Rosiglitazone/metformin double combinations generally gives (allusion quotation with the dosage of 1/500 to 4/1000mg (every day twice) Type dosage strengths is 1/500,2/500,4/500,2/1000 and 4/1000mg).
Pioglitazone/metformin double combinations is generally (every with 15/500mg (once-or twice-a-day) to 15/850mg Days three times) dosage give (typical doses specification is 15/500 and 15/850mg).
Non-sulfonylurea Insulin secretagogues Nateglinide generally accompanies meal to give (up to the dosage of 60 to 120mg 360mg/ days, typical doses specification was 60 and 120mg)；Repaglinide generally accompanies meal to give (up to the dosage of 0.5 to 4mg 16mg/ days, typical doses specification was 0.5,1 and 2mg).Repaglinide/metformin double combinations can be with 1/500 and 2/850mg Dosage strengths use.
Acarbose generally accompanies meal to give with the dosage of 25 to 100mg.Miglitol is generally accompanied with the dosage of 25 to 100mg Meal gives.
Reducing the composition of medicine example of lipid concentration in blood is HMG-CoA-reductase inhibitor, such as simvastatin, Atorvastatin, lovastatin, fluvastatin, pravastatin, Pitavastatin and rosuvastatin；Fibrates, such as benzene prick shellfish Spy, fenofibrate, clofibrate, gemfibrozil, etofibrate and etofylline clofibrate (etofyllinclofibrate)；Nicotinic acid and Derivant, such as acipimox；PPAR-alfa agonists；PPAR-delta agonists；Acetyl-coenzyme A: cholesterol acyltransferase (ACAT；EC 2.3.1.26) inhibitor, such as avasimibe；Cholesterol absorption inhibitor, such as Ezetimibe (ezetimib)；It is bound to the material of bile acid, such as colestyramine, colestipol and colesevelam；Bile acid transport suppresses Agent；HDL regulates active substance, such as D4F, reverse D4F (reverse D4F), LXR regulation active substance and FXR regulation activity Material；CETP inhibitor, such as torcetrapib (torcetrapib), JTT-705/ Da Chepu (dalcetrapib) or from WO The compound 12 (anacetrapib) of 2007/005572；Ldl receptor regulator；MTP inhibitor (such as lomitapide) and ApoB100 antisense RNA.
The dosage of atorvastatin is usually 1mg to 40mg or 10mg to 80mg, once a day.
The example of the composition of medicine reduced blood pressure is beta blocker, such as atenolol, bisoprolol, celiprolol, U.S. Tuo Luoer and carvedilol；Diuretic, such as hydrochlorothiazide, chlortalidone, xipamide, furosemide, piretanide, torasemide, Spironolactone, eplerenone, amiloride and triamterene；Calcium channel blocker, such as amlodipine, nifedipine, Ni Qundi Flat, nisoldipine, nicardipine, felodipine, lacidipine, lercanidipine (lercanipidine), Manidipine, Yi La Horizon, nilvadipine, verapamil, gallopamil and diltiazem；ACE inhibitor, such as ramipril, lisinopril, west Draw Puli, quinapril, captopril, enalapril, benazepril, perindopril, fosinopril and trandolapril；And blood Angiotensin II receptor blocking agent (ARB), such as telmisartan, Candesartan, valsartan, losartan, irbesartan, Aomei sand Smooth and Eprosartan.
The dosage of telmisartan is usually 20mg to 320mg every day or 40mg to 160mg.
In elevating blood, the composition of medicine example of HDL concentration is cetp (CETP) inhibitor；Interior sebum Enzyme inhibitor；ABC1 regulator；LXR alpha-2 antagonists；LXR beta-agonists；PPAR-delta agonists；LXR α/β regulator and increase carry fat The expression of protein A-I and/or the material of plasma concentration.
It is sibutramine for treating the composition of medicine example of obesity；Orlistat (tetrahydrolipstatin) (orlistat)；West is for Li Sita (cetilistat), A Licimo (alizyme)；Right sweet smell Fluorine Lamine；Axokine (axokine)；Cannabined receptor 1 antagonist, such as CB1 antagonist ACOMPLIA (rimonobant)； MCH-1 receptor antagonist；MC4 receptor stimulating agent；NPY5 and NPY2 antagonist (such as Wei lifibrate (velneperit))；β 3-AR agonist, such as SB-418790 and AD-9677；5HT2c receptor stimulating agent, such as APD 356/ lorcaserin (lorcaserin)；Tubocurarine inhibitor；Acrp30 and fat even element；Stearyl CoA desaturase (SCD1) inhibitor；Fat Fat acid synthase (FAS) inhibitor；Cck receptor agonist；Polypeptide lattice that quinoline (Ghrelin) receptor modulators；Pyy 3-36；A Li Novel receptor antagonist；And Te Suofenxin (tesofensine)；And the general product of cloth (bupropion)/naltrexone, the general product of cloth/azoles Buddhist nun Husky amine, topiramate/phentermine and the double combinations of Pramlintide/metreleptin.
Treating atherosclerotic composition of medicine example is PLA 2 inhibitors；Tyrosine kinase inhibitor (50mg To 600mg), such as PDGF-receptor-kinases (sees EP-A-564409, WO 98/35958, US 5093330, WO 2004/ 005281 and WO 2006/041976)；OxLDL antibody and oxLDL vaccine；apoA-1Milano；ASA；And VCAM-1 suppression Agent.
The scope of the present invention is not limited to detailed description of the invention as herein described.In addition to those described herein, those Technical staff should be understood the various amendments of the present invention by the disclosure of invention.These amendments are intended to be included in the right enclosed In the range of requirement.
The full text of all patent applications cited herein is all hereby incorporated by reference.
Other embodiment of the present invention, feature and advantage can be understood by following example.Following example are for implement Example mode exemplarily illustrates the principle of the present invention, rather than is any limitation as it.
Pharmacological examples
The DPP-4 inhibitor of following example display present invention or the combination beneficial effect to glycemic control.
Embodiment 1:
According to first embodiment, at male Zucker Diabetic Fatty (ZDF) rat (ZDF/ of overnight fasting Crl-LeprfaOral glucose tolerance test is carried out in).Take blood by afterbody and obtain the front blood sample of administration.Survey with blood glucose meter Amount blood glucose, and animal random packet is used for blood sugar test (often organizing n=5).Subsequently, each group accept that single oral gives independent Medium (containing 0.5% hydroxyethyl cellulose aqueous solution of 3mM HCl and 0.015%Polysorbat 80) or press down containing DPP-4 Preparation or the second or the third antidiabetic drug or DPP-4 inhibitor add the second and add optionally the third antidiabetic drug The medium of combination.Or, also can test after repeatedly giving each medicine, need the long period could to demonstrate Produce obvious antidiabetic effect, such as the situation of thiazolidinedione.After to drug compound 30 minutes, animal receiving port Take glucose load (2g/kg).Glucose stimulate after 30 minutes, 60 minutes, 90 minutes, 120 minutes and 180 minutes, measure Blood glucose in tail blood.Quantifying glucose fluctuation is carried out by calculating reactive glucose AUC.Data are with meansigma methods ± SEM table Show.Bilateral unpaired Students t test method (Student's t test) is used to come statistical matched group and activity group.
Embodiment 2:
According to second embodiment, body weight be about 200g overnight fasting male Sprague Dawley rat (Crl: CD (SD)) in carry out oral glucose tolerance test.Take blood by afterbody and obtain the front blood sample of administration.Blood is measured with blood glucose meter Sugar, and animal random packet is used for blood sugar test (often organizing n=5).Subsequently, each group accepts the independent medium that single oral gives (containing 0.5% hydroxyethyl cellulose aqueous solution of 0.015%Polysorbat 80) or containing DPP-4 inhibitor or the second Or the third antidiabetic drug or DPP-4 inhibitor add the second and add the medium of the optionally combination of the third antidiabetic drug. Or, each group accepts independent medium that single oral gives or adds the 3rd containing DPP-4 inhibitor or the second antidiabetic drug Plant antidiabetic drug or DPP-4 inhibitor adds the medium that the second antidiabetic drug adds the combination of the third antidiabetic drug.Or Person, also can test after each medicine of multiple dosing, needs the long period to occur and thiazolidinedione to explain The most obvious antidiabetic effect in situation.After to drug compound 30 minutes, animal accepted oral glucose load (2g/kg).Glucose stimulate after 30 minutes, 60 minutes, 90 minutes and 120 minutes, measure the blood glucose in tail blood.Pass through Calculate reactive glucose AUC and carry out quantifying glucose fluctuation.Data represent with meansigma methods ± S.E.M.Carried out by student's t method of inspection Statistical.
Embodiment 3: treatment pre-diabetes
Can use clinical research test the present invention pharmaceutical composition or combination treatment with pathologic fasting glucose and/ Or effect that glucose tolerance is reduced in the pre-diabetes of feature.In the research in short period of time (such as 2-4 week), pass through Fasting glucose value and/or after the meal or Road test (oral after set dining is measured after the treatment of research terminates period Glucose tolerance test or food tolerance test) after dextrose equivalent, and by its with research start before these values and/or These values of placebo group relatively check treatment successful.Additionally, fructosamine can be measured before treatment and afterwards (fructosamine) value, and compare with initial value and/or placebo value.On an empty stomach or the significantly reducing of non-empty stomach glucose content Demonstrate therapeutic efficiency.In the research of long term (12 weeks or more than 12 weeks), by measure HbA1c value and initial value and/ Or placebo class value relatively tests treatment successful.Compared with initial value and/or placebo value, significantly changing of HbA1c value Demonstrate the DPP-4 inhibitor of the present invention or combine for the effect treating pre-diabetes.
Embodiment 4: prevent dominant type ii diabetes
Treatment pathologic fasting glucose and/or glucose tolerance reduce (pre-diabetes) patient and also pursue prevention transformation Become the target of dominant type ii diabetes.Therapeutic efficiency can be investigated, wherein with the medicine group of the present invention in comparative clinical research Compound or combination or placebo or non-drug therapy or other medicines are through the treatment pre-diabetes of overlength period (such as 1-5) Patient.During treating and at the end for the treatment of, examine by measuring fasting glucose and/or Road test (such as oGTT) Test, to determine that how many patients show dominant type ii diabetes, i.e. fasting glucose content 125mg/dl and/or according to the 2 of oGTT One hour value > 199mg/dl.Compared with treatment with other form a kind of, during with DPP-4 inhibitor or the combined therapy of the present invention, aobvious Show substantially reducing of dominant type ii diabetes patient populations, it was demonstrated that prevention is transformed into the merit of overt diabetes from pre-diabetes Effect.
Embodiment 5: treatment type ii diabetes
With pharmaceutical composition or the combined therapy type ii diabetes patient of the present invention, except glucose metabolism situation is produced Outside quickly improving, the most long-term prevention metabolism status deteriorates.Can be with the pharmaceutical composition of the present invention or combined therapy long term (such as 3 months to 1 years or even 1 to 6 year) and the patient that compares with the patient treated with other antidiabetic medicine see Observe this result.If observing, fasting glucose and/or HbA1c value do not increase or are only increased slightly, then evidence shows and with it The patient of its antidiabetic medicine treatment compares, and treats successfully.If it is compared with the patient treated with other medicines, the least by hundred The glucose metabolism situation with the pharmaceutical composition of the present invention or the patient of combined therapy of proportion by subtraction deteriorates (such as HbA1c value increasing To > 6.5% or > 7%) need to treat with extra oral antidiabetic thing or insulin or insulin analog to instruction Degree, obtains evidence the most further and shows to treat successfully.
Embodiment 6: treatment insulin resistant
In the clinical research of different time length (such as 2 thoughtful 12 months), use hyperinsulinemia-normal blood Treatment successful is checked in sugar clamp research.Compared with initial value or placebo group or the group giving different therapy, at research knot During bundle, glucose infusion rate significantly raises, it was demonstrated that the DPP-4 inhibitor of the present invention, pharmaceutical composition or combined therapy islets of langerhans Effect of element opposing.
Embodiment 7: treatment hyperglycemia
In the clinical research of different time length (such as 1 day to 24 months), by measuring fasting glucose or non-NULL Abdomen glucose (the most after the meal or after oGTT Road test or limit have meal after) inspection treatment success in hyperglycemic subject Property.Compared with initial value or placebo group or the group giving different therapy, these glucoses during studying or at the end of research Value significantly reduces, it was demonstrated that the DPP-4 inhibitor of the present invention, pharmaceutical composition or effect of combined therapy hyperglycemia.
Embodiment 8: prevention blood capillary or macrovascular complications
With DPP-4 inhibitor, pharmaceutical composition or combined therapy type ii diabetes or the pre-diabetes patient of the present invention, Prevent or decrease microvascular complication (such as diabetic neuropathy, diabetic retinopathy, diabetic kidney Disease, diabetic foot, diabetic ulcer) or macrovascular complications (such as myocardial infarction, acute coronary syndrome, shakiness Sizing angina pectoris, stable angina pectoris, apoplexy, peripheral occlusive arterial disease, cardiomyopathy, heart failure, arrhythmia, blood vessel Restenosis) or reduce the risk developing these complication.Pharmaceutical composition or combination with the present invention are long-term (such as 1-6) Treatment type ii diabetes or pre-diabetes patient, and with patient's ratio of other antidiabetic medicine or placebo treatment Relatively.Compared with the patient with other antidiabetic medicine or placebo treatment, the negligible amounts of solitary or multiple complication, Show to treat successfully.In the situation of big vascular events, diabetic foot and/or diabetic ulcer, by medical history and many Plant method of testing number of computations.In the situation of diabetic retinopathy, by optical fundus being carried out the illumination of computer control And assessment or other ophtamological method determine treatment successful.In the situation of diabetic neuropathy, except medical history And outside Clinical Laboratory, it be also possible to use the tuning fork such as calibrated and measure nerve conduction velocity.About diabetic nephropathy, can grind Before studying carefully beginning, during research and at the end of research, study following parameter: albumin secretion, creatinine clearance, serum creatine Acid anhydride value, serum creatinine value double the time used until must dialyse the time used.
Embodiment 9: treatment metabolism syndrome
Can be by measuring fasting glucose or non-empty stomach in the clinical research of different time length (such as 12 thoughtful 6 years) Glucose (the most after the meal or after oGTT Road test or limit have meal after) or HbA1c value are tested the DPP-4 of the present invention and are suppressed Effect of agent, pharmaceutical composition or combination.Compared with initial value or placebo group or the group giving different therapy, in the research phase Between or research at the end of these dextrose equivalents or HbA1c value significantly reduce, it was demonstrated that the combination of active substance or active substance is controlled Treat effect of metabolism syndrome.The example is and the initial value studied when starting or the patient treated with placebo or different therapy Group is compared, and shrinks pressure and/or diastolic pressure reduction, plasma triglyceride reduction, T-CHOL or LDL-C reduces, HDL gallbladder is solid Alcohol raises or body weight reduces.
Embodiment 10a: prevention NODAT and/or PTMS and NODAT/PTMS related complication
With the patient after the medicine composite for curing organ transplantation of the present invention, prevent NODAT and/or PTMS and be correlated with also Send out the development of disease.Effect for the treatment of can be investigated, wherein with pharmaceutical composition or the comfort of the present invention in comparative clinical research Agent or non-drug therapy or other medicines be patient or the firm patient transplanted before ultra-long time (such as 1-5) treatment is transplanted. During therapy and at the end of therapy, will evaluation NODAT, PTMS, blood capillary and macrovascular complications, transplant rejection, infection and Dead sickness rate.The quantity of the patient experiencing these complication substantially reduces, it was demonstrated that prevention NODAT, PTMS and relevant also Send out effect of disease development.
Embodiment 10b:NODAT and/or the Prevention of PTMS, postpone or reduce related complication
Use medicine composite for curing NODAT and/or the PTMS patient of the present invention, prevent, postpone or decrease NODAT/ The development of PTMS related complication.Effect for the treatment of can be investigated, wherein with the medicine group of the present invention in comparative clinical research Compound or placebo or non-drug therapy or other medicines are suffered from through ultra-long time (such as 1-5) treatment NODAT and/or PTMS Person.During therapy and at the end of therapy, by evaluation blood capillary and macrovascular complications, transplant rejection, infection and death send out Sick rate.The quantity of the patient experiencing these complication substantially reduces, it was demonstrated that prevention, postpones or reduces NODAT and/or PTMS phase Close effect of complication development.
Embodiment 12: treatment hyperuricemia
Uric acid content is increased to the patient of more than normal value (more than 8.3mg/dL or 494 μm ol/L) or has gout or pain Wind arthritis medical history and uric acid content are more than 6.0mg/dL or patient's future onset gout of 357 μm ol/L or gouty joint Scorching risk is high, and the risk suffering from cardiovascular disease increases.Purpose can be provided to be to reduce the therapy of serum uric acid, its For prevention future onset or happen suddenly gout or the method for gouty arthritis.Additionally, reduction serum uric acid can reduce suffers from the heart The risk of angiopathy.For this purpose it is proposed, with the pharmaceutical composition of the present invention or placebo or non-drug therapy or other medicines warp Ultra-long time (such as 6 months to 4 years) treatment has the patient of metabolic arthritis content or has gout or gouty arthritis medical history Patient.During treating and at the end for the treatment of, by measuring sending out of serum uric acid and gout or gouty arthritis Check as number of times.Compared with different types of therapy, when with the medicine composite for curing of the present invention, uric acid is reduced to Below 6.0mg/dL and/or gout or gouty arthritis attack times reduce, it was demonstrated that pharmaceutical composition have prevention gout or Gouty arthritis outbreak or effect for the treatment of hyperuricemia.
Embodiment 13: BI 1356 improves hepatic steatosis in rodent model
Hepatic steatosis is the mark of type ii diabetes patient, and hides the pathology of non-alcoholic fatty liver disease (NAFLD). BI 1356 is the inhibitor of the dipeptidyl peptidase 4 (DPP-4) of selectivity and non-renal excretion.Obesity mould in diet induced In type (DIO, feeding 2 or 3 months), have studied the effect using BI 1356 (3 and 30mg/kg/ days, n=10) to treat 4 weeks. Pass through NMR (Nuclear Magnetic Resonance) spectrum (MRS) in vivo and analyze the triglyceride detection liver lipids content of liver in vitro.DPP-4 lives Property is significantly inhibited (p < 0.001), compared with the control, and its suppressed 67%-80% and 79%-89% (respectively 3 Hes 30mg/kg).After OGTT test, blood sugar level (AUC) notable (p < 0.01) is suppressed 16%-20% (3mg/kg/ days) and 20%- 26% (30mg/kg/ days).Hepatic fat content (MRS detection) significantly reduces, except 3mg/kg dosage 2nd month feed In the DIO mice of food.Hepatic fat content (MRS) to be substantially reducing at the 2nd week for the treatment of the most visible.Measured by MRS Liver lipids content is r2=0.565 (p < 0.0001) with the phase relation of the content of triglyceride of the liver measured in vitro.
In studying at the 3rd, treat (3mg/kg/ days) 14 days post analysis ob/ob mices at BI 1356, and carry out blind Method histological score (seriousness of fat content and grade, the labelling of inflammation).DPP-4 activity inhibited 80% and blood glucose AUC reduces 25%.Histological score discloses contrast comparison (3 ± 0.18, n=10), BI 1356 group (2.2 ± 0.13, n =9, p < 0.01) less hepatic steatosis and inflammation.In a word, in two different rodent models, BI 1356 Significantly reduce hepatic fat content and histology NAFLD, it may be possible to caused by the insulin sensitiser effect that liver is special.Liver The reverse support of steatosis uses BI 1356 in type ii diabetes and NAFLD patient.
Example of formulations
Can be similar to the embodiment of the following preparation that method as is generally known in the art obtains for illustrating in greater detail the present invention, Rather than limit the invention in the content of these embodiments.Term " active substance " represents one or more chemical combination of the present invention Thing, i.e. represent the DPP-4 inhibitor of the present invention or the second or the third antidiabetic compound or two or three these live The combination of sexual element, is selected from the combination as listed by table 1 or 2.Other suitable preparation of DPP-4 inhibitor BI 1356 Can as application WO 2007/128724 in disclosed in preparation, the disclosure of this application is incorporated herein by reference.Other Other suitable preparation of DPP-4 inhibitor is the commercially available preparation buied, or above " prior art " paragraph is quoted special Preparation described in profit application, or those preparations described in document, such as existing periodical " Rote" (Germany) or Preparation disclosed in " Physician's Desk Reference ".
Embodiment 1: every 10ml contains the dry ampoule of 75mg active substance
Composition:
Active substance 75.0mg
Mannitol 50.0mg
Water for injection supplies 10.0ml
Preparation:
Active ingredient and mannitol are dissolved in the water.After encapsulation, by solution lyophilization.Molten in order to prepare instant Liquid, is dissolved in product in water for injection.
Embodiment 2: every 2ml contains the dry ampoule of 35mg active substance
Composition:
Active substance 35.0mg
Mannitol 100.0mg
Water for injection supplies 2.0ml
Preparation:
Active substance and mannitol are dissolved in the water.After encapsulation, by solution lyophilization.
In order to prepare instant solution, product is dissolved in water for injection.
Embodiment 3: containing the tablet of 50mg active substance
Composition:
Preparation:
(1), (2) and (3) and is pelletized together with the aqueous solution of (4).Add in drying granulated material (5).Thus mixture compressed tablets, these tablets are that biplanar, bilateral has facet and has segmentation indenture on side.
Tablet diameters: 9mm.
Embodiment 4: containing the tablet of 350mg active substance
Preparation:
(1), (2) and (3) and is pelletized together with the aqueous solution of (4).Add in drying granulated material (5).Thus mixture compressed tablets, these tablets are that biplanar, bilateral has facet and has segmentation indenture on side.
Tablet diameters: 12mm.
Embodiment 5: containing the capsule of 50mg active substance
Composition:
Preparation:
(1) is ground with (3).Under being vigorously mixed, this abrasive material is added to the mixture of (2) and (4).Fill out at capsule Fill in this mixture of powders encapsulation to No. 3 hard gelatin capsules in machine.
Embodiment 6: containing the capsule of 350mg active substance
Composition:
Preparation:
(1) is ground with (3).Under being vigorously mixed, this abrasive material is added to the mixture of (2) and (4).Fill out at capsule Fill in this mixture of powders encapsulation to No. 0 hard gelatin capsule in machine.
In sum, the application includes but not limited to techniques below item:
1. pharmaceutical composition, it comprises:
(a) DPP-4 inhibitor,
And, optionally,
B (), selected from the second antidiabetic drug of group G3, how it includes biguanide, thiazolidinedione, sulfonylureas, row, α-Portugal Polyglycoside enzyme inhibitor and GLP-1 analog, and, optionally,
C (), selected from the third antidiabetic drug being different from (b) of group G3, it includes biguanide, thiazolidinedione, sulphonyl Urea, row how, alpha-glucosidase inhibitor and GLP-1 analog,
Or its pharmaceutically acceptable salt.
2. the pharmaceutical composition of technology item 1, it comprises:
(a) DPP-4 inhibitor,
And, optionally,
(b) selected from group G3 the second antidiabetic drug, it include biguanide (especially metformin), thiazolidinedione, Sulfonylureas, row how, alpha-glucosidase inhibitor and GLP-1 analog, and, optionally,
C () is different from the third antidiabetic drug of (b), it is selected from metformin, sulfonylureas, pioglitazone, Luo Gelie Ketone, repaglinide, Nateglinide, acarbose, voglibose, miglitol and GLP-1 analog,
Or its pharmaceutically acceptable salt.
3. the pharmaceutical composition of technology item 1, it comprises:
(a) DPP-4 inhibitor,
And, optionally,
(b) the second antidiabetic drug, its selected from metformin, sulfonylureas, pioglitazone, rosiglitazone, repaglinide, Nateglinide, acarbose, voglibose, miglitol and GLP-1 analog, and, optionally,
(c) selected from group G3 the third antidiabetic drug being different from (b), it include biguanide (especially metformin), Thiazolidinedione, sulfonylureas, row how, alpha-glucosidase inhibitor and GLP-1 analog,
Or its pharmaceutically acceptable salt.
4. the pharmaceutical composition of technology item 1,2 or 3, it comprises
(a) DPP-4 inhibitor,
And, optionally,
(b) the second antidiabetic drug, it is selected from metformin, sulfonylureas and pioglitazone, and, optionally,
C () is different from the third antidiabetic drug of (b), it is selected from metformin, sulfonylureas, pioglitazone, Luo Gelie Ketone, repaglinide, Nateglinide, acarbose, voglibose, miglitol and GLP-1 analog,
Or its pharmaceutically acceptable salt.
5. the pharmaceutical composition any one of technology item 1-4, it comprises
(a) DPP-4 inhibitor,
And, optionally,
(b) the second antidiabetic drug, it is selected from metformin and pioglitazone, and, optionally,
C () is different from the third antidiabetic drug of (b), it is selected from metformin, sulfonylureas and pioglitazone,
Or its pharmaceutically acceptable salt.
6. the pharmaceutical composition of technology item 1,2 or 3, wherein said the second and/or the third antidiabetic drug are selected from two First biguanide, pioglitazone, rosiglitazone, troglitazone, ciglitazone, glibenclamide, tolbutamide, glimepiride, lattice arrange Pyrazine, gliquidone, Glibornuride, insoral, glisoxepide, gliclazide, Nateglinide, repaglinide, Mitiglinide, Acarbose, voglibose, miglitol, Exenatide, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], taspoglutide, semaglutide, albiglutide and profit Department's Shandong peptide, or the pharmaceutically acceptable salt of a kind of above-mentioned therapeutic agent.
7. the pharmaceutical composition any one of technology item 1-6, wherein said DPP-4 inhibitor is selected from group G2, including Li La Row spit of fland, sitagliptin, vildagliptin, Egelieting, BMS-477118, carmegliptin, melogliptin, gosogliptin, teneligliptin And dutogliptin, or the pharmaceutically acceptable salt of a kind of above-mentioned DPP-4 inhibitor, or its prodrug.
Pharmaceutical composition any one of the most above-mentioned technology item, also includes one or more pharmaceutically acceptable carriers.
Pharmaceutical composition any one of the most above-mentioned technology item, it is characterised in that described compositions is suitable for simultaneously or sequentially making Use described composition.
Pharmaceutical composition any one of the most above-mentioned technology item, it is characterised in that described composition is with single dosage form or respective Exist with separate dosage forms.
Pharmaceutical composition any one of 11. above-mentioned technology items, it is characterised in that described DPP-4 inhibitor and described second Plant antidiabetic drug to exist with single dosage form, and the third antidiabetic drug described exists with separate dosage forms.
12. prevent dysbolismus, the method slowing down its progress, postponing or treat this dysbolismus in the patient needed, Described dysbolismus is selected from type i diabetes, type ii diabetes, glucose tolerance reduction, impaired fasting glucose, hyperglycemia, meal Rear hyperglycemia, overweight, obesity and metabolism syndrome, it is characterised in that the DPP-4 inhibitor of technology item 7, and, optionally Ground, the second antidiabetic drug any one of technology item 1-6, and, optionally, the third any one of technology item 1-6 Antidiabetic drug is with combination, including alternately giving described patient.
13. improve glycemic control in the patient needed and/or reduce fasting plasma glucose, Post-prandial plasma glucose And/or the method for glycosylated hemoglobin HbA1c, it is characterised in that the DPP-4 inhibitor of technology item 7, and, optionally, skill The second antidiabetic drug any one of art item 1-6, and, optionally, the third the anti-glycosuria any one of technology item 1-6 Sick medicine is with combination, including alternately giving described patient.
14. prevent, slow down, postpone or the reduction of reverses glucose tolerance, impaired fasting glucose, islets of langerhans in the patient needed Element opposing and/or the method being progressed to type ii diabetes by metabolism syndrome, it is characterised in that the DPP-4 inhibitor of technology item 7, And, optionally, the second antidiabetic drug any one of technology item 1-6, and, optionally, any one of technology item 1-6 The third antidiabetic drug with combination, including alternately giving described patient.
15. need patient in prevent following disease or obstacle, slow down this disease or obstacle progress, postpone or treat This disease or the method for obstacle: diabetic complication, such as cataract and blood capillary and macrovascular diseases, such as nephropathy, view Film pathological changes, neuropathy, tissue ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, instability Type angina pectoris, stable angina pectoris, apoplexy, peripheral occlusive arterial disease, cardiomyopathy, heart failure, arrhythmia and blood vessel Restenosis, it is characterised in that the DPP-4 inhibitor of technology item 7, and, optionally, the second any one of technology item 1-6 resists Rezulin, and, optionally, the third antidiabetic drug any one of technology item 1-6 is with combination, including alternately giving institute State patient.
16. in the patient needed, reduce body weight and/or body fat or prevention body weight and/or body fat increases or Promote to reduce body weight and/or the method for body fat, it is characterised in that the DPP-4 inhibitor of technology item 7, and, optionally, skill The second antidiabetic drug any one of art item 1-6, and, optionally, the third the anti-glycosuria any one of technology item 1-6 Sick medicine is with combination, including alternately giving described patient.
17. prevent, slow down, postpone or treat pancreatic beta cell in the patient needed degenerates and/or Pancreatic beta cells function Reduce and/or improve and/or recover or protect Pancreatic beta cells function and/or the method recovering pancreatic insulin secretory function, It is characterized in that the DPP-4 inhibitor of technology item 7, and, optionally, the second anti-diabetic any one of technology item 1-6 Medicine, and, optionally, the third antidiabetic drug any one of technology item 1-6 is with combination, including alternately giving described trouble Person.
18. prevent, slow down, postpone or treat and extremely accumulated, by liver or ectopic fat, the disease caused in the patient needed Disease or the method for disease, it is characterised in that the DPP-4 inhibitor of technology item 7, and, optionally, any one of technology item 1-6 The second antidiabetic drug, and, optionally, the third antidiabetic drug any one of technology item 1-6 is with combination, including handing over For giving described patient.
19. keep and/or improve insulin sensitivity and/or treatment or prevention hyperinsulinemia in the patient needed And/or the method for insulin resistant, it is characterised in that the DPP-4 inhibitor of technology item 7, and, optionally, in technology item 1-6 The second antidiabetic drug of any one, and, optionally, the third antidiabetic drug any one of technology item 1-6 is with group Close, including alternately giving described patient.
Pharmaceutical composition any one of 20. technology items 1 to 11 is used for realizing following mesh in the patient needed in preparation Medicine in purposes:
-prevention selected from following dysbolismus, slow down the progress of this dysbolismus, postpone or treat this dysbolismus: I type Diabetes, type ii diabetes, glucose tolerance reduction, impaired fasting glucose, hyperglycemia, post prandial hyperglycemia, overweight, fat Disease and metabolism syndrome；Or
-improve glycemic control and/or reduce fasting plasma glucose, Post-prandial plasma glucose and/or the blood red egg of glycosylation White HbA1c；Or
-prevent, slow down, postpone or reverses glucose tolerance reduces, insulin resistant and/or metabolism syndrome are in progress into II Patients with type Ⅰ DM；Or
-prevention selected from following disease or obstacle, slow down this disease or obstacle progress, postpone or treat this disease or barrier Hinder: diabetic complication, such as cataract and blood capillary and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, Learning and memory is impaired, neural degeneration or cognitive disorder, cardiovascular or cerebrovascular disease, tissue ischemia, diabetic foot or ulcer, Arteriosclerosis, hypertension, endothelial function disturbance, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable Type angina pectoris, apoplexy, peripheral occlusive arterial disease, cardiomyopathy, heart failure, arrhythmia and vascular restenosis；Or
-reduce body weight and/or body fat or prevention body weight and/or body fat increase or promote to reduce body weight and/ Or body fat；Or
-prevent, slow down, postpone or treat pancreatic beta cell degenerate and/or Pancreatic beta cells function reduce, and/or improve and/ Or recover or protect Pancreatic beta cells function and/or recover pancreatic insulin secretory function；Or
-prevent, slow down, postpone or treat and extremely accumulated the disease caused or disease by liver or ectopic fat；Or
-keep and/or improve insulin sensitivity and/or treatment or prevention hyperinsulinemia and/or insulin resistant； Or
The diabetes (NODAT) of-prevention new outbreak after transplanting and/or the metabolism syndrome (PTMS) after transplanting, slow down it It is in progress, postpones or treat these diseases；Or
-prevent, postpone or reduce NODAT and/or PTMS related complication, including blood capillary and macrovascular diseases and thing Part, transplant rejection, infection and death；Or
-treatment hyperuricemia and hyperuricemia associated conditions.
Method any one of 21. technology item 12-19 or the purposes of technology item 20, wherein said patient suffers from one for diagnosis Plant or the individuality of the multiple disease selected from overweight, obesity, visceral obesity and abdominal fatness.
Method any one of 22. technology item 12-19 or the purposes of technology item 20, wherein said patient is a kind of for display, The individuality of the following disease of two or more:
A () fasting glucose or serum glucose concentration are more than 100 or 110mg/dL, especially greater than 125mg/dL；
B () Post-prandial plasma glucose equals to or more than 140mg/dL；
C () HbA1c value equals to or more than 6.5%, especially equal to or more than 7.0%.
Method any one of 23. technology item 12-19 or the purposes of technology item 20, wherein said patient for exist a kind of, Two kinds, three kinds or the individuality of multiple following disease:
(a) obesity, visceral obesity and/or abdominal fatness,
(b) triglyceride blood content >=150mg/dL,
(c) female patient HDL-cholesterol blood level < 40mg/dL and male patient < 50mg/dL,
D () shrinks pressure >=130mm Hg and diastolic pressure >=85mm Hg,
(e) fasting glucose content >=100 or 110mg/dL.
Method any one of 24. technology item 12-19 or the purposes of technology item 20, although wherein said patient drinks Although food and exercise therapy or carry out the monotherapy of the second or the third antidiabetic drug, but glycemic control is not filled Point.
Method any one of 25. technology item 12-19 or the purposes of technology item 20, although wherein said patient drinks Although food and exercise therapy or carry out the dual therapy of the second and the third antidiabetic drug, but glycemic control is not filled Point.
Double combinations method any one of 26. technology item 12-19 or the purposes of the double combinations of technology item 20, Qi Zhongsuo Although carried out diet and exercise therapy although stating patient or carried out DPP-4 inhibitor or the second or the third anti-diabetic Although any one monotherapy or carry out the dual therapy of the second and the third antidiabetic drug in medicine, but glycemic control The most insufficient.
Triple combined methods any one of 27. technology item 12-19 or the purposes of three recombinations of technology item 20, Qi Zhongsuo Although carried out diet and exercise therapy although stating patient or carried out DPP-4 inhibitor or the second or the third anti-diabetic Although any one monotherapy or carried out in DPP-4 inhibitor, the second and the third antidiabetic drug two in medicine Plant the combination treatment of medicine, but glycemic control is the most insufficient.
Pharmaceutical composition, combination, method or purposes any one of 28. above-mentioned technology items, wherein said DPP-4 inhibitor For BI 1356.

Claims (10)

1. pharmaceutical composition, it comprises:
(a) DPP-4 inhibitor,
And, optionally,
B (), selected from the second antidiabetic drug of group G3, how it includes biguanide, thiazolidinedione, sulfonylureas, row, phlorose Glycosides enzyme inhibitor and GLP-1 analog, and, optionally,
C (), selected from the third antidiabetic drug being different from (b) of group G3, it includes biguanide, thiazolidinedione, sulfonylureas, row How, alpha-glucosidase inhibitor and GLP-1 analog,
Or its pharmaceutically acceptable salt.
2. the pharmaceutical composition of claim 1, it comprises:
(a) DPP-4 inhibitor,
And, optionally,
B (), selected from the second antidiabetic drug of group G3, it includes biguanide (especially metformin), thiazolidinedione, sulphonyl Urea, row how, alpha-glucosidase inhibitor and GLP-1 analog, and, optionally,
C () is different from the third antidiabetic drug of (b), it is selected from metformin, sulfonylureas, pioglitazone, rosiglitazone, auspicious Ge Lienai, Nateglinide, acarbose, voglibose, miglitol and GLP-1 analog,
Or its pharmaceutically acceptable salt.
3. the pharmaceutical composition of claim 1, it comprises:
(a) DPP-4 inhibitor,
And, optionally,
B () the second antidiabetic drug, it is selected from metformin, sulfonylureas, pioglitazone, rosiglitazone, repaglinide, those lattice Row how, acarbose, voglibose, miglitol and GLP-1 analog, and, optionally,
C (), selected from the third antidiabetic drug being different from (b) of group G3, it includes biguanide (especially metformin), thiazole Alkane diketone, sulfonylureas, row how, alpha-glucosidase inhibitor and GLP-1 analog,
Or its pharmaceutically acceptable salt.
4. the pharmaceutical composition of claim 1,2 or 3, it comprises
(a) DPP-4 inhibitor,
And, optionally,
(b) the second antidiabetic drug, it is selected from metformin, sulfonylureas and pioglitazone, and, optionally,
C () is different from the third antidiabetic drug of (b), it is selected from metformin, sulfonylureas, pioglitazone, rosiglitazone, auspicious Ge Lienai, Nateglinide, acarbose, voglibose, miglitol and GLP-1 analog,
Or its pharmaceutically acceptable salt.
5. the pharmaceutical composition any one of claim 1-4, it comprises
(a) DPP-4 inhibitor,
And, optionally,
(b) the second antidiabetic drug, it is selected from metformin and pioglitazone, and, optionally,
C () is different from the third antidiabetic drug of (b), it is selected from metformin, sulfonylureas and pioglitazone,
Or its pharmaceutically acceptable salt.
6. the pharmaceutical composition of claim 1,2 or 3, wherein said the second and/or the third antidiabetic drug are selected from diformazan Biguanide, pioglitazone, rosiglitazone, troglitazone, ciglitazone, glibenclamide, tolbutamide, glimepiride, lattice row pyrrole Piperazine, gliquidone, Glibornuride, insoral, glisoxepide, gliclazide, Nateglinide, repaglinide, Mitiglinide, Ah Card ripple sugar, voglibose, miglitol, Exenatide, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], taspoglutide, semaglutide, albiglutide and Li Si Shandong peptide, or the pharmaceutically acceptable salt of a kind of above-mentioned therapeutic agent.
7. the pharmaceutical composition any one of claim 1-6, wherein said DPP-4 inhibitor is selected from group G2, including Li Lalie Spit of fland, sitagliptin, vildagliptin, Egelieting, BMS-477118, carmegliptin, melogliptin, gosogliptin, teneligliptin and Dutogliptin, or the pharmaceutically acceptable salt of a kind of above-mentioned DPP-4 inhibitor, or its prodrug.
8. the pharmaceutical composition any one of the claims, also includes one or more pharmaceutically acceptable carriers.
9. the pharmaceutical composition any one of the claims, it is characterised in that described compositions is suitable for simultaneously or sequentially using Described composition.
10. the pharmaceutical composition any one of the claims, it is characterised in that described composition with single dosage form or each with Separate dosage forms exists.
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